Traditional Chinese medicine composition for tonifying qi, nourishing yin, strengthening body resistance, dispersing blood stasis and eliminating stagnation and preparation method thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine pharmacy, and discloses a traditional Chinese medicine composition for reinforcing qi, nourishing yin, strengthening the body resistance, dispersing blood stasis and eliminating stagnation and a preparation method thereof, and the composition is prepared from 16 raw materials including astragalus membranaceus, oyster, kelp, selfheal, radix ranunculi ternati, salvia chinensis, caulis spatholobi and the like. The preparation method comprises the following steps: extracting lipophilic components and preparing a supramolecular inclusion compound; converting the oysters into calcium citrate precursor reaction liquid, and extracting other hydrophilic components by using the calcium citrate precursor reaction liquid as a solvent; and after extraction, rapidly raising the temperature to induce heat shock phase change, adsorbing impurities by using precipitated calcium citrate crystals, filtering at high temperature, and mixing with an inclusion compound. Pharmacodynamic experiments show that the composition can significantly inhibit collagen deposition and pathological score of bleomycin-induced pulmonary nodule model mice, and shows excellent microcirculation improvement, anti-inflammation and immunoregulation effects in qi deficiency and blood stasis and lung inflammatory injury models.

Description

Technical Field

[0001] This invention relates to the field of traditional Chinese medicine pharmaceutical technology, and in particular to a traditional Chinese medicine composition that invigorates qi, nourishes yin, strengthens the body's resistance, eliminates blood stasis, and disperses nodules, and its preparation method. Background Technology

[0002] With the development of modern imaging technology, the detection rate of diseases such as pulmonary nodules, thyroid nodules, and lymphadenopathy is on the rise. In traditional Chinese medicine clinical practice, these conditions often fall under the categories of "goiter," "scrofula," or "phlegm nodules," and their pathogenesis is often complex, manifesting as a coexistence of deficiency of vital energy and phlegm-blood stasis. Currently, commonly used Chinese herbal formulas focus on "attacking the pathogenic factors" by softening and dispersing nodules and promoting blood circulation to remove blood stasis. While this can reduce the size of nodules to some extent, it often neglects the patient's underlying constitution of deficiency of both qi and yin. Long-term and excessive use of blood-breaking and stasis-removing or bitter-cold purgative drugs can easily deplete the body's vital energy, leading to damage to the spleen and stomach or recurrence of the disease, making it difficult to achieve a comprehensive treatment effect.

[0003] In pharmaceutical formulation processes, traditional decoction methods for compound preparations containing marine shellfish (such as oysters) and algae (such as kelp) face significant technical obstacles. Because kelp and other algae are rich in alginic acid, it readily reacts with calcium ions dissolved from oysters during the heating extraction process, forming insoluble and highly viscous calcium alginate gel. This gelation not only significantly increases the viscosity of the liquid, making filtration difficult, but also forms a barrier layer on the surface of the herbs, hindering the diffusion and dissolution of water-soluble active ingredients such as astragalus polysaccharides, thereby reducing the utilization rate of the raw materials.

[0004] Furthermore, these compound prescriptions typically contain herbs rich in volatile oils or fat-soluble components, such as cinnamon twig, dried tangerine peel, and five-spice powder. Conventional water extraction not only fails to effectively extract these fat-soluble components but also easily leads to the loss of heat-sensitive volatile oils with steam during decoction. Conversely, using only alcohol extraction causes the precipitation and loss of water-soluble active ingredients such as polysaccharides and amino acids. Existing preparation technologies struggle to simultaneously achieve efficient dissolution of hydrophilic components, stable retention of lipophilic components, and effective removal of high-molecular-weight impurities such as proteins in a single process. The resulting medicinal solutions often suffer from poor clarity and are prone to precipitation during long-term storage, leading to stability issues. Summary of the Invention

[0005] The technical problem solved by this invention is that existing traditional Chinese medicine compound formulas for treating pulmonary nodules and scrofula often have problems such as low dissolution rate of active ingredients and easy loss of volatile components. Furthermore, they are difficult to simultaneously address the "symptom" of eliminating nodule solids and the "root" of improving qi and yin deficiency, resulting in unstable efficacy or easy recurrence.

[0006] To address the above problems, the present invention provides the following technical solution:

[0007] In a first aspect, the present invention provides a traditional Chinese medicine composition for invigorating qi, nourishing yin, supporting the body's resistance, and resolving blood stasis and masses, which is made from raw materials comprising the following parts by weight:

[0008] Astragalus membranaceus 300-600 parts, Oyster shell 250-350 parts, Laminaria japonica 150-250 parts, Prunella vulgaris 150-250 parts, Cat's claw grass 150-250 parts, Hedyotis diffusa 150-200 parts, Spatholobus suberectus 200-300 parts, Forsythia suspensa 100-150 parts, Ophiopogon japonicus 100-150 parts, Coix lacryma-jobi 200-300 parts, Cinnamomum cassia 50-70 parts, Trogopterus xanthipes 100-140 parts, Citrus reticulata 70-90 parts, Platycodon grandiflorus 60-100 parts, Zingiber officinale 30-50 parts, Citrus aurantium 70-90 parts.

[0009] By adopting the above technical solution, this traditional Chinese medicine composition is based on the pathological mechanism of pulmonary nodules with deficiency of both qi and yin and mutual binding of phlegm and blood stasis, and achieves both symptomatic and root-cause treatment through specific drug combinations.

[0010] Specifically, the formula heavily uses Astragalus membranaceus as the principal ingredient to replenish the Qi of the spleen and lungs, thereby nourishing the source of Qi and blood production. By replenishing Qi, it promotes blood circulation. When Qi is sufficient, body fluids are distributed normally, thus blocking the source of phlegm and turbidity regeneration. Oyster shell and kelp are the principal ingredients together. Both are salty and can soften hardness, and cold and can clear heat. They work together to soften and dissipate pathological nodule products.

[0011] The formula uses Prunella vulgaris and Cat's Claw Grass as assistant herbs, both of which specifically enter the liver and lung meridians to clear liver fire, disperse stagnation, and intervene in the abnormal distribution of body fluids and the formation of phlegm nodules caused by liver qi stagnation. Hedyotis diffusa is also used as an assistant herb, which has the dual effects of promoting blood circulation and removing blood stasis, as well as clearing heat and detoxifying, improving the microcirculation disorders and inflammatory reactions in the nodules. Spatholobus suberectus is also used as an assistant herb, which nourishes and promotes blood circulation, relaxes muscles and tendons, and unblocks meridian channels to help the medicine reach the affected area. Forsythia suspensa and Ophiopogon japonicus are used as assistant herbs together. Forsythia suspensa clears heat and detoxifies to disperse nodules, while Ophiopogon japonicus nourishes yin and moistens the lungs to prevent dryness. This formula not only clears the heat toxins generated by phlegm and blood stasis, but also prevents pungent and dispersing drugs from consuming lung yin.

[0012] The formula is supplemented with five-spice powder to invigorate blood circulation and relieve pain, thus resolving blood stasis; tangerine peel and coix seed to regulate qi, strengthen the spleen, dry dampness and resolve phlegm, thus helping to eliminate the source of phlegm production; cinnamon twig and ginger to warm and unblock the meridians, and promote yang qi, using the warming effect to promote the flow of phlegm and blood stasis caused by cold and dampness, and to restrain the influence of cold and cooling drugs on the yang qi of the spleen and stomach; and immature bitter orange to regulate qi, relieve chest tightness, and promote circulation to eliminate bloating.

[0013] Platycodon grandiflorus is used as the guiding herb, utilizing its ability to carry other herbs upwards to direct the medicinal power of the entire formula to the lesions in the lungs and neck, and to clear the lungs and eliminate phlegm.

[0014] The combined effects of all the herbs in the formula are to invigorate qi and nourish yin to strengthen the body's resistance, soften and disperse nodules to treat the symptoms, and promote blood circulation and remove blood stasis to improve the pathological environment of the lungs and promote the absorption of nodules.

[0015] Furthermore, the weight parts of the raw materials are as follows:

[0016] Astragalus membranaceus 450 parts, Oyster shell 300 parts, Laminaria japonica 200 parts, Prunella vulgaris 200 parts, Cat's claw grass 200 parts, Hedyotis diffusa 180 parts, Spatholobus suberectus 250 parts, Forsythia suspensa 120 parts, Ophiopogon japonicus 120 parts, Coix lacryma-jobi 250 parts, Cinnamomum cassia 60 parts, Trogopterus xanthipes 120 parts, Citrus reticulata peel 80 parts, Platycodon grandiflorus 80 parts, Zingiber officinale 40 parts, Citrus aurantium 80 parts.

[0017] By adopting the above technical solution, the components achieve a better synergistic effect under this ratio. Under this ratio, the qi-tonifying effect of Astragalus membranaceus can support the circulation of blood-activating and softening drugs without causing qi stagnation, while the softening power of Oyster shell and Laminaria japonica is suitable for counteracting the hard texture of old nodules. Furthermore, the proportion of cold and hot drugs is balanced, reducing the side effects of coldness damaging the stomach or warmth damaging yin, making it suitable for long-term use to treat chronic pulmonary nodules.

[0018] Furthermore, the raw material also contains pharmaceutically acceptable excipients, which include at least anhydrous citric acid and hydroxypropyl-β-cyclodextrin.

[0019] The introduction of anhydrous citric acid and hydroxypropyl-β-cyclodextrin through the above technical solutions is a targeted improvement based on the physicochemical properties of the raw medicinal materials.

[0020] On the one hand, hydroxypropyl-β-cyclodextrin can form inclusion complexes with medicinal materials containing volatile oils and highly lipophilic components (such as cinnamon twig, tangerine peel, ginger, five-spice powder, immature bitter orange peel, and rock hemp seed). This inclusion complexation improves the solubility and dispersion stability of poorly soluble active ingredients in aqueous media, reducing their volatilization loss or oxidative degradation during extraction and formulation.

[0021] On the other hand, anhydrous citric acid reacts chemically with oysters rich in calcium carbonate, converting the insoluble inorganic calcium into calcium citrate and calcium hydrogen citrate. This not only increases the dissolution rate of calcium ions but also provides a material basis for utilizing temperature-sensitive properties to remove impurities in subsequent preparation processes.

[0022] Furthermore, the amount of anhydrous citric acid used is 0.7 to 1.2 times the weight of the oyster; the amount of hydroxypropyl-β-cyclodextrin used is 0.1 to 0.4 times the total weight of cinnamon twig, dried tangerine peel, ginger, five-spice powder, immature bitter orange, rock hemp, and ginger.

[0023] By employing the above technical solutions, the ratio of anhydrous citric acid to oyster shell is controlled to ensure the full conversion of calcium in the oyster shell into calcium citrate precursor. Simultaneously, a suitable pH environment is maintained in the system to prevent excessive acidity from damaging glycoside components or insufficient acidity from leading to incomplete conversion. Controlling the ratio of hydroxypropyl-β-cyclodextrin ensures the inclusion rate of lipophilic components while avoiding excessive excipients that could affect drug loading, thus achieving efficient loading and protection of the active ingredient.

[0024] Furthermore, the traditional Chinese medicine composition is an oral liquid, compound preparation, or syrup.

[0025] By adopting the above technical solutions, liquid dosage forms facilitate the dispersion and absorption of drugs in the gastrointestinal tract, meeting the need for rapid blood and qi circulation required for the treatment of pulmonary nodules; at the same time, oral liquids or mixtures are easy to control for uniformity through industrial means, ensuring batch-to-batch quality stability.

[0026] Secondly, the present invention provides a method for preparing a traditional Chinese medicine composition that invigorates qi, nourishes yin, strengthens the body's resistance, and dissipates blood stasis and nodules, comprising the following steps:

[0027] S1. Preparation of supramolecular inclusion complex suspension of lipophilic components: Cinnamon twig, tangerine peel, ginger, five-spice powder, bitter orange peel, and rock hemp seed were extracted with alcohol. Cyclodextrin solution was added to the extract for inclusion, and the ethanol was recovered to obtain the inclusion complex suspension.

[0028] S2. Preparation of calcium citrate precursor reaction solution: Oysters are crushed and mixed with water, citric acid is added, and the mixture is reacted under heating conditions. The pH value is adjusted to obtain a precursor reaction solution containing calcium citrate microcrystals and calcium hydrogen citrate.

[0029] S3, Blocking Extraction: The precursor reaction solution obtained in S2 is used as the extraction solvent, and the remaining hydrophilic medicinal components are added for extraction at 75-80℃;

[0030] S4. Thermal phase change and filtration: After extraction, the temperature of the liquid is rapidly raised to 100-103℃ and maintained at a slight boiling state to induce the precipitation of calcium citrate crystals; then a filter aid is added, and filtration is carried out under the condition that the temperature of the liquid is higher than 90℃, and the hot filtrate is collected.

[0031] S5. Mixing: Combine the inclusion complex suspension obtained in S1 with the hot filtrate obtained in S4, and adjust the pH value to obtain the final product.

[0032] By adopting the above technical solution, this invention utilizes the thermodynamic differences of multiphase systems and supramolecular chemistry principles to solve the problems of hindered dissolution of effective components and difficulty in removing impurities in traditional compound preparation.

[0033] Firstly, this invention utilizes competitive coordination and gel-blocking mechanisms to improve extraction efficiency. Kelp and other medicinal materials are rich in alginic acid, which readily combines with calcium ions dissolved from oysters during conventional decoction, forming insoluble and highly viscous calcium alginate gels that hinder mass transfer of the medicinal solution. This invention introduces citrate ions as competitive ligands by pre-preparing a calcium citrate precursor reaction solution. At the extraction temperature, the stability of the complex formed by citric acid and calcium ions is higher than the binding force between calcium ions and alginic acid. This competitive coordination effect shields calcium ions from direct contact with alginic acid, effectively blocking gel formation, significantly reducing the viscosity of the extraction system, and ensuring the full dissolution of macromolecular active substances such as astragalus polysaccharides.

[0034] Secondly, in-situ purification is achieved using a thermo-induced phase transition mechanism driven by reverse solubility. Calcium citrate exhibits unique reverse solubility characteristics, meaning its solubility decreases with increasing temperature. During the low-temperature extraction stage, it maintains relatively high solubility; however, when the temperature is rapidly increased to a near-boiling state after extraction, its solubility drops sharply, resulting in extremely high supersaturation and inducing the explosive precipitation of calcium citrate crystals. These newly formed crystals possess extremely high specific surface area and surface energy, enabling them to capture fine suspended impurities such as proteins and mucus in situ through electrostatic adsorption and van der Waals forces. Subsequently, high-temperature thermal filtration removes the crystals containing the adsorbed impurities, achieving physical-chemical purification and significantly improving the clarity and stability of the formulation.

[0035] Thirdly, the dispersion problem of poorly soluble components is solved by utilizing the host-guest supramolecular inclusion mechanism. The resinous components in *Wulingzhi* and *Shijianchuan*, as well as the volatile oil of *Guizhi*, are strongly hydrophobic. Utilizing the cyclic cavity structure of hydroxypropyl-β-cyclodextrin (externally hydrophilic and internally hydrophobic), these hydrophobic molecules are included within the cavity in an alcohol-water co-solvent system. After removing the ethanol, the inclusion complex is stably dispersed in the aqueous phase by the hydrophilic groups on the outside of the cyclodextrin, thus solving the problem of easy precipitation and wall adhesion of resinous drugs in aqueous formulations.

[0036] Preferably, in step S1, the specific operation of inclusion is as follows: hydroxypropyl-β-cyclodextrin aqueous solution is directly added to the alcohol extract, the volume fraction of ethanol in the system is adjusted to 30-40%, the temperature is lowered to 40-50°C, and a high-shear homogenizer is used to shear the mixture at a speed of 2000-3000 rpm for 20-30 minutes.

[0037] By adopting the above technical solutions and controlling the volume fraction of ethanol and temperature, the solvent polarity and molecular thermal motion state can be adjusted to optimize the binding energy between host and guest molecules. Combined with high-shear homogenization, the collision probability between drug molecules and cyclodextrin cavities is increased, significantly improving the inclusion rate and the uniformity of the inclusion complex.

[0038] Preferably, in step S2, the specific preparation operation is as follows: oysters are added to water, anhydrous citric acid is added, the temperature is raised to 70-80°C, and the mixture is stirred at a constant temperature for 30-50 minutes. After the reaction is completed, the pH value of the system is adjusted to 4.2-4.8; wherein, the weight ratio of anhydrous citric acid to oysters is (0.7-1.13):1.

[0039] By employing the above technical solution, specific temperature and pH conditions ensure that the crystal structure and solubility characteristics of the calcium citrate precursor meet the requirements of subsequent thermally induced phase transitions. Precise pH control not only guarantees the complexation stability of calcium ions but also avoids hydrolytic damage to acid-sensitive components such as astragalus polysaccharides added later due to an overly acidic environment.

[0040] Preferably, in step S4, the conditions for the thermal phase change are: heating the liquid to 102-103°C at a heating rate of 2.5°C / min or higher, and maintaining it under micro-pressure for 10-20 minutes; the filtration operation is as follows: at the end of maintaining the boiling state, adding 0.5%-1.0% of diatomaceous earth equivalent to the volume of the liquid into the vessel, stirring evenly, and then pumping the liquid into the preheated filtration equipment while it is still hot, controlling the temperature of the filtration medium to be not lower than 95°C.

[0041] By employing the above technical solution, rapid heating creates an instantaneous high supersaturation in the system, promoting the generation of numerous fine crystal nuclei and enhancing the specific surface area effect of impurity adsorption. Maintaining a slight boiling state and controlling high-temperature filtration are to prevent the redissolution of calcium citrate due to temperature reduction, ensuring that the crystals adsorbed with impurities are completely retained in the filter cake, thereby guaranteeing the purity of the filtrate.

[0042] Thirdly, the present invention provides the application of the traditional Chinese medicine composition described above, which invigorates qi, nourishes yin, strengthens the body, eliminates blood stasis, and disperses nodules, in the preparation of a medicine for treating pulmonary nodules, thyroid nodules, breast nodules, scrofula, or phlegm nodules caused by deficiency of both qi and yin and mutual obstruction of phlegm and blood stasis.

[0043] By adopting the above technical solutions, this invention is based on the treatment principle of treating different diseases with the same method in traditional Chinese medicine. It targets lesions in different locations such as pulmonary nodules, thyroid nodules, breast nodules and lymph node enlargement, and focuses on their common pathological basis, namely, the deficiency of the body's vital energy leads to abnormal distribution of body fluids, which condenses into phlegm, and then leads to blood stasis and the mutual binding of phlegm and blood stasis to form tangible masses.

[0044] The application mechanism of this traditional Chinese medicine composition in the preparation of the above-mentioned drugs is mainly reflected in three aspects:

[0045] Firstly, it regulates the body's immune function through herbs such as Astragalus membranaceus and Ophiopogon japonicus. Targeting the pathological essence of Qi and Yin deficiency, the medicinal components can enhance the body's immune surveillance and clearance capabilities, improve the constitution prone to nodules caused by immune imbalance, and fundamentally inhibit the proliferation and recurrence of nodules.

[0046] Secondly, it inhibits abnormal tissue proliferation through drugs such as oyster shell, kelp, and prunella vulgaris. Pharmacological studies have shown that the active ingredients of these drugs, which soften and disperse nodules, can intervene in the excessive accumulation of extracellular matrix, inhibit the proliferation of fibrous tissue and collagen deposition, thereby promoting the softening and shrinking of existing fibrotic nodules or proliferative masses.

[0047] Thirdly, the microcirculation of the lesion is improved by using drugs such as *Scutellaria baicalensis*, *Spatholobus suberectus*, and *Trogopterus xanthipes*. Targeting the hemorheological abnormalities often associated with nodules, the drug components can reduce blood viscosity, dilate microvessels, improve local blood perfusion, accelerate the excretion of metabolic products, and promote the dissipation of pathological products accumulated due to phlegm and blood stasis.

[0048] In summary, this application demonstrates that by combining the regulation of systemic function with intervention in local pathological changes, drugs can achieve comprehensive treatment of the aforementioned nodular diseases.

[0049] In summary, the present invention has at least one of the following beneficial technical effects:

[0050] 1. The traditional Chinese medicine composition of this invention is based on the pathogenesis of qi and yin deficiency and phlegm-blood stasis, and achieves both symptomatic and root-cause treatment through scientific formulation. The formula heavily utilizes Astragalus membranaceus to tonify qi and strengthen the exterior, combined with Ophiopogon japonicus to nourish yin and moisten dryness, establishing a foundation for strengthening the body's resistance and consolidating its foundation. It is combined with Oyster shell, Laminaria japonica, and Prunella vulgaris to soften and disperse nodules, and with Hedyotis diffusa and Trogopterus xanthipes to invigorate blood and remove blood stasis. This strategy of combining attack and tonification not only utilizes softening and blood-activating drugs to eliminate pathological products such as pulmonary nodules and lymphadenopathy, but also improves the body's immune microenvironment through tonifying drugs, preventing recurrence of the disease due to qi deficiency, and significantly improving the clinical efficacy for chronic nodular diseases. In particular, as shown in Test Example 6, in a bleomycin-induced pulmonary nodule mouse model, the composition of the present invention exhibited excellent anti-fibrotic and nodule-dispersing abilities, reducing the lung coefficient of model mice by 40.4%, the hydroxyproline content reflecting collagen deposition by 55.6%, and improving the Ashcroft pathological score by 62.5%. Its comprehensive intervention effect is superior to or close to that of the first-line clinical drug pirfenidone, which strongly confirms the scientific nature and effectiveness of the "invigorating qi and resolving phlegm, softening hardness and eliminating blood stasis" strategy of this formula.

[0051] 2. The preparation method of this invention effectively solves the gelation problem when co-decocting medicinal materials rich in alginate with mineral-based medicinal materials by introducing citric acid competitive coordination technology. Utilizing the strong complexing ability of citrate ions to calcium ions, the reaction pathway for the formation of insoluble calcium alginate gel between calcium ions in oysters and alginate in kelp is blocked. This improvement reduces the viscosity of the extraction system, eliminates the hindering effect of the gel layer on the mass transfer of the medicinal solution, and significantly increases the dissolution rate of macromolecular active ingredients such as astragalus polysaccharides, thereby improving the utilization rate of the raw medicinal materials.

[0052] 3. This invention combines thermally induced phase change purification with supramolecular inclusion technology, significantly improving the clarity and stability of the formulation. Utilizing the reverse solubility characteristics of calcium citrate, it is instantaneously precipitated through high-temperature thermal shock and adsorbed in situ to remove high-molecular impurities such as proteins and pectin from the drug solution, achieving low-cost, high-efficiency physical impurity removal. Simultaneously, hydroxypropyl-β-cyclodextrin is used to encapsulate volatile oils and resinous components in medicinal materials such as cinnamon twig and five-spice powder, solving the problem of easy precipitation and oxidation of poorly soluble components in aqueous formulations, ensuring the long-term quality stability of the finished formulation. Detailed Implementation

[0053] The present invention will be further described in detail below with reference to specific embodiments, but the implementation of the present invention is not limited thereto.

[0054] The main raw materials and reagents used in the following examples and comparative examples have the following sources and specifications. Reagents not specifically mentioned are all commercially available analytical grade or higher grade products.

[0055] Astragalus membranaceus, oyster shell, kelp, prunella vulgaris, hedyotis diffusa, chicken blood vine, forsythia suspensa, ophiopogon japonicus, cat's claw grass, coix seed, cinnamon twig, trogopterus xanthipes, tangerine peel, platycodon grandiflorus, ginger, and immature bitter orange are all commercially available pharmaceutical-grade processed medicinal materials that meet the requirements of the Pharmacopoeia of the People's Republic of China. Anhydrous citric acid, CAS No. 77-92-9, purity ≥99.5%; sodium citrate, CAS No. 6132-04-3, purity ≥99.0%; hydroxypropyl-β-cyclodextrin, CAS No. 128446-35-5, average degree of substitution (DS) 4.2–5.5, pharmaceutical grade; diatomaceous earth, CAS No. 61790-53-2, pharmaceutical-grade filter aid, particle size distribution (D50) 10–30 μm.

[0056] Preparation Example 1:

[0057] This preparation example provides a method for preparing a suspension of supramolecular inclusion complexes of lipophilic components, including the following steps:

[0058] Weigh out 60g of cinnamon twigs, 80g of dried tangerine peel, 40g of ginger, 120g of five-spice powder, 80g of immature bitter orange peel, and 180g of rockwort. Mix them evenly, pulverize them through a 30-mesh sieve, and put them into an extraction tank. Add 3920ml of 70% ethanol aqueous solution, turn on the heating reflux device, control the extraction temperature at 65℃, and extract for 1.5 hours. After extraction, add 300g of 40% hydroxypropyl-β-cyclodextrin aqueous solution (dry weight 120g) directly to the extract, and add an appropriate amount of deionized water to adjust the ethanol volume fraction in the system to about 35%. Lower the system temperature to 45℃ and keep it constant. Turn on the high-shear homogenizer, set the speed to 2500rpm, and shear for 25 minutes. After processing, place the mixture in a vacuum concentration tank and recover ethanol at 50℃ and a vacuum of -0.08MPa until the distillate has no alcohol odor, and obtain a milky white supramolecular inclusion suspension for later use.

[0059] Preparation Example 2:

[0060] This preparation example provides a method for preparing a suspension of supramolecular inclusion complexes of lipophilic components, including the following steps:

[0061] Weigh out 60g of cinnamon twigs, 80g of dried tangerine peel, 40g of ginger, 120g of five-spice powder, 80g of immature bitter orange peel, and 180g of rockwort. Mix them evenly, pulverize them through a 20-mesh sieve, and put them into an extraction tank. Add 3360ml of 60% ethanol aqueous solution, turn on the heating reflux device, control the extraction temperature at 60℃, and extract for 2.0 hours. After extraction, add 240g of 30% hydroxypropyl-β-cyclodextrin aqueous solution (corresponding to 72g dry weight) to the extract, and add an appropriate amount of deionized water to adjust the ethanol volume fraction in the system to about 30%. Lower the system temperature to 40℃ and keep it constant. Turn on the high-shear homogenizer, set the speed to 2000rpm, and shear for 20 minutes. After processing, place the mixture in a vacuum concentration tank and recover ethanol at 55℃ and a vacuum of -0.08MPa until the distillate has no alcohol odor, and obtain a milky white supramolecular inclusion suspension for later use.

[0062] Preparation Example 3:

[0063] This preparation example provides a method for preparing a suspension of supramolecular inclusion complexes of lipophilic components, including the following steps:

[0064] Weigh out 60g of cinnamon twigs, 80g of dried tangerine peel, 40g of ginger, 120g of five-spice powder, 80g of immature bitter orange peel, and 180g of rockwort. Mix them evenly, pulverize them through a 40-mesh sieve, and put them into an extraction tank. Add 4480ml of 75% ethanol aqueous solution, turn on the heating reflux device, control the extraction temperature at 70℃, and extract for 1.5 hours. After extraction, add 360g of 50% hydroxypropyl-β-cyclodextrin aqueous solution (corresponding to 180g dry weight) to the extract, and add an appropriate amount of deionized water to adjust the ethanol volume fraction in the system to about 40%. Lower the system temperature to 50℃ and keep it constant. Turn on the high-shear homogenizer, set the speed to 3000rpm, and shear for 30 minutes. After processing, place the mixture in a vacuum concentration tank and recover ethanol at 45℃ and a vacuum of -0.08MPa until the distillate has no alcohol odor, and obtain a milky white supramolecular inclusion suspension for later use.

[0065] Preparation Example 4:

[0066] This preparation example provides a method for preparing the calcium citrate precursor reaction solution, including the following steps:

[0067] Weigh 300g of oyster slices, pulverize them through a 100-mesh sieve using an ultra-micro pulverizer, and put them into a reaction vessel. Add 3000ml of deionized water. Turn on the stirrer and set the speed to 100rpm. Add 280g of anhydrous citric acid, heat to 75℃, and maintain a constant temperature while stirring for 40 minutes. During this period, a large number of bubbles were observed to be generated and gradually subsided. The reaction solution was a uniformly dispersed milky white colloidal suspension. After the reaction was completed, add an appropriate amount of sodium hydroxide solution or concentrated sodium citrate solution to adjust the pH of the system to 4.5. A colloidal precursor reaction solution containing calcium citrate microcrystals and calcium hydrogen citrate was obtained and set aside for later use.

[0068] Preparation Example 5:

[0069] This preparation example provides a method for preparing the calcium citrate precursor reaction solution, including the following steps:

[0070] Weigh 300g of oyster slices, pulverize them through an 80-mesh sieve using an ultra-micro pulverizer, and put them into a reaction vessel. Add 2400ml of deionized water. Turn on the stirrer and set the speed to 80rpm. Add 210g of anhydrous citric acid, heat to 70℃, and maintain a constant temperature while stirring for 30 minutes. During this period, observe the overflow of bubbles. After the reaction is complete, add an appropriate amount of sodium hydroxide solution or concentrated sodium citrate solution to adjust the pH of the system to 4.8, and obtain a colloidal precursor reaction solution containing calcium citrate microcrystals and calcium hydrogen citrate for later use.

[0071] Preparation Example 6:

[0072] This preparation example provides a method for preparing the calcium citrate precursor reaction solution, including the following steps:

[0073] Weigh 300g of oyster slices, pulverize them through a 120-mesh sieve using an ultra-micro grinder, and put them into a reaction vessel. Add 3600ml of deionized water. Turn on the stirrer and set the speed to 120rpm. Add 340g of anhydrous citric acid, heat to 80℃, and maintain a constant temperature while stirring for 50 minutes. During this period, observe the overflow of bubbles. After the reaction is complete, add an appropriate amount of sodium hydroxide solution or concentrated sodium citrate solution to adjust the pH of the system to 4.2, and obtain a colloidal precursor reaction solution containing calcium citrate microcrystals and calcium hydrogen citrate for later use.

[0074] Example 1:

[0075] This embodiment provides a method for preparing a traditional Chinese medicine composition that invigorates qi, nourishes yin, strengthens the body's resistance, and dissipates blood stasis and nodules, including the following steps:

[0076] (1) Take the total amount of the lipophilic component supramolecular inclusion complex suspension obtained in Preparation Example 1 and set it aside.

[0077] (2) Take the total amount of the calcium citrate precursor reaction solution obtained in Preparation Example 4 (including 300g of oyster feed) and put it into the extraction tank. Add the remaining hydrophilic medicinal materials: Astragalus membranaceus 450g, Laminaria japonica 200g, Prunella vulgaris 200g, Uncaria rhynchophylla 200g, Spatholobus suberectus 250g, Forsythia suspensa 120g, Ophiopogon japonicus 120g, Coix lacryma-jobi 250g, Platycodon grandiflorus 80g; then add 17L of deionized water so that the liquid-solid ratio in the extraction system is about 10:1 (based on the total weight of the hydrophilic medicinal materials).

[0078] (3) Raise the temperature inside the reactor to 78°C and maintain this temperature for 2.0 hours of blocking extraction. During this time, keep stirring at 60 rpm. At this time, the system is in colloidal form and no obvious gel aggregation occurs.

[0079] (4) After extraction, turn on the high-pressure steam heating of the reactor jacket and raise the temperature of the liquid in the reactor to 102°C within 10 minutes at a heating rate of 2.5°C / min. Then maintain the micro-boiling state under micro-pressure for 15 minutes to induce the in-situ explosive precipitation of calcium citrate crystals.

[0080] (5) During the last 2 minutes of maintaining the boiling state, add pharmaceutical grade diatomaceous earth (about 150g) equivalent to 0.8% of the liquid volume to the vessel and stir quickly to form a rigid filter cake skeleton.

[0081] (6) While the liquid is hot (the temperature of the liquid is >95℃), pump the liquid into the preheated plate and frame filter press for filtration. The filtrate flows directly into the heat-insulated storage tank and the filter cake is discarded.

[0082] (7) Combine the supramolecular inclusion complex suspension prepared in step (1) with the hot filtrate prepared in step (6) in a mixing tank, stir evenly, add an appropriate amount of sodium carbonate solution to adjust the pH value to 6.5, and then degas, fill and sterilize under vacuum to obtain the final product.

[0083] Example 2:

[0084] This embodiment provides a method for preparing a traditional Chinese medicine composition that invigorates qi, nourishes yin, strengthens the body's resistance, and dissipates blood stasis and nodules, including the following steps:

[0085] (1) Take the full amount of the lipophilic component supramolecular inclusion complex suspension obtained in Preparation Example 2 and set it aside.

[0086] (2) Take the total amount of the calcium citrate precursor reaction solution obtained in Preparation Example 5 (including 300g of oyster feed) and put it into the extraction tank. Add the remaining hydrophilic medicinal materials: Astragalus membranaceus 300g, Laminaria japonica 150g, Prunella vulgaris 150g, Cat's claw grass 150g, Spatholobus suberectus 200g, Forsythia suspensa 100g, Ophiopogon japonicus 100g, Coix lacryma-jobi 200g, Platycodon grandiflorus 60g; then add 12L of deionized water to make the total liquid-solid ratio of the system about 9:1.

[0087] (3) Raise the temperature inside the reactor to 75°C and maintain this temperature for 1.5 hours of blockage extraction, while stirring at 50 rpm.

[0088] (4) After extraction, turn on the jacket heating of the reactor to quickly raise the temperature of the liquid in the reactor to 100°C and maintain the temperature for 15 minutes to induce the precipitation of calcium citrate crystals by utilizing the reverse solubility characteristics.

[0089] (5) During the last 3 minutes of maintaining the high temperature, add pharmaceutical grade diatomaceous earth (about 65g) equivalent to 0.5% of the liquid volume and stir to disperse;

[0090] (6) While the liquid is hot (the temperature of the liquid is >90°C), pump the liquid into a preheated filter press for filtration, collect the filtrate, and discard the filter cake.

[0091] (7) Combine the supramolecular inclusion complex suspension prepared in step (1) with the hot filtrate obtained in step (6), stir evenly, adjust the pH value to 6.0, and then proceed with routine processing.

[0092] Example 3:

[0093] This embodiment provides a method for preparing a traditional Chinese medicine composition that invigorates qi, nourishes yin, strengthens the body's resistance, and dissipates blood stasis and nodules, including the following steps:

[0094] (1) Take the total amount of the lipophilic component supramolecular inclusion complex suspension obtained in Preparation Example 3 and set it aside.

[0095] (2) Take the total amount of the calcium citrate precursor reaction solution obtained in Preparation Example 6 (including 300g of oyster feed) and put it into the extraction tank. Add the remaining hydrophilic medicinal materials: 600g of Astragalus membranaceus, 250g of Laminaria japonica, 250g of Prunella vulgaris, 250g of Cat's Scratch Grass, 300g of Spatholobus suberectus, 150g of Forsythia suspensa, 150g of Ophiopogon japonicus, 300g of Coix lacryma-jobi, and 100g of Platycodon grandiflorus. Then add 21L of deionized water to make the total liquid-solid ratio of the system about 10:1.

[0096] (3) Raise the temperature inside the reactor to 80°C and maintain this temperature for 2.5 hours for blockage extraction, while stirring at 80 rpm.

[0097] (4) After extraction, turn on the jacket of the reactor to heat at full speed, quickly raise the temperature of the liquid in the reactor to 103°C, and maintain a slight boiling state for 20 minutes to fully induce the precipitation of calcium citrate phase transition;

[0098] (5) During the last 2 minutes of maintaining the boiling state, add pharmaceutical grade diatomaceous earth (about 240g) equivalent to 1.0% of the liquid volume and stir quickly until uniform;

[0099] (6) While the liquid is hot (the temperature of the liquid is >98°C), pump the liquid into a preheated ceramic membrane filter or filter press for filtration, collect the filtrate, and discard the filter cake.

[0100] (7) Combine the supramolecular inclusion complex suspension prepared in step (1) with the hot filtrate obtained in step (6), stir evenly, adjust the pH value to 7.0, and then proceed with routine processing.

[0101] Example 4:

[0102] This embodiment provides a method for preparing a traditional Chinese medicine composition that invigorates qi, nourishes yin, strengthens the body's resistance, and dissipates blood stasis and nodules, including the following steps:

[0103] (1) Take the total amount of the lipophilic component supramolecular inclusion complex suspension obtained in Preparation Example 1 and set it aside.

[0104] (2) Take the total amount of the calcium citrate precursor reaction solution prepared in Example 4, add the same weight of the remaining hydrophilic medicinal material component as in Example 1, and add 17L of deionized water.

[0105] (3) Raise the temperature inside the reactor to 78°C and maintain this temperature for 2.0 hours;

[0106] (4) After extraction, clean steam is directly introduced for heating. The latent heat of steam is used to make the temperature of the liquid material reach 102°C instantaneously within 5 minutes and maintain it for 10 minutes.

[0107] (5) Then add diatomaceous earth (about 110g) equivalent to 0.6% of the liquid volume and stir for 1 minute;

[0108] (6) Immediately carry out heat preservation and pressure filtration, and control the temperature of the filter medium to not be lower than 95℃ to prevent calcium citrate from redissolving;

[0109] (7) Combine the supramolecular inclusion complex suspension prepared in step (1) with the hot filtrate obtained in step (6), adjust the pH value to 6.8, and then proceed with routine processing.

[0110] Comparative Example 1:

[0111] Compared with Example 1, the difference is that anhydrous citric acid and sodium citrate were not added to the raw material components, and the preparation of calcium citrate precursor solution was omitted in the preparation process. Specifically, the oyster slices were crushed and directly mixed with other hydrophilic medicinal materials such as astragalus and kelp, and deionized water was added for extraction in step (3). The extraction temperature and time were the same as in Example 1, and the remaining steps and parameters were the same.

[0112] Comparative Example 2:

[0113] Compared with Example 1, the difference is that the principal ingredient, oyster, was not added to the raw material components, and the preparation step of calcium citrate precursor solution was omitted in the preparation process. Specifically, anhydrous citric acid and sodium citrate were directly added to water to dissolve, and then other hydrophilic medicinal materials were added for extraction. The remaining steps and parameters were the same.

[0114] Comparative Example 3:

[0115] Compared with Example 1, the difference lies in the filtration operation temperature in step (6). Specifically, after adding diatomaceous earth and mixing it evenly in step (5), the liquid is naturally cooled to 50°C and then pumped into a filter press for filtration. The remaining steps and parameters are the same.

[0116] Comparative Example 4:

[0117] Compared with Example 1, the difference is that the high-temperature thermal phase change step (4) is omitted. The specific operation is as follows: after the extraction in step (3), the temperature of the liquid is kept at 78°C. No heating and micro-boiling treatment is performed. The subsequent addition of diatomaceous earth and filtration are carried out directly. The other steps and parameters are the same.

[0118] Comparative Example 5:

[0119] Compared with Example 1, the difference is that hydroxypropyl-β-cyclodextrin was not added in step (1). The specific operation is as follows: after the lipophilic medicinal material component is extracted by ethanol reflux, the ethanol is directly concentrated under reduced pressure to recover the ethanol until there is no alcohol taste, and a concentrated liquid containing a large amount of oily precipitate is obtained. Then it is combined with the aqueous filtrate. The remaining steps and parameters are the same.

[0120] Comparative Example 6:

[0121] Compared with Example 1, the difference is that in step (6), instead of relying on in-situ crystal precipitation to remove impurities, conventional flocculants are used. The specific operation is as follows: the heat shock heating in step (4) is omitted. After extraction, the liquid is cooled to 40°C, and a conventional amount of chitosan flocculant is added to remove impurities. After standing, it is filtered. The remaining steps and parameters are the same.

[0122] Comparative Example 7:

[0123] Compared with Example 1, the difference is that Astragalus membranaceus, the principal ingredient, was not added to the raw material components, while the other steps and parameters are the same.

[0124] Comparative Example 8:

[0125] Compared with Example 1, the difference is that the principal drug, kelp, was not added to the raw material components, while the other steps and parameters are the same.

[0126] Comparative Example 9:

[0127] Compared with Example 1, the difference is that the medicinal herbs Prunella vulgaris and Cat's Claw Grass were not added to the raw material components, while the other steps and parameters are the same.

[0128] Comparative Example 10:

[0129] Compared with Example 1, the difference is that Platycodon grandiflorus was not added to the raw material components, while the other steps and parameters are the same.

[0130] Comparative Example 11:

[0131] Compared with Example 1, the difference is that the adjuvants Wulingzhi and Shijianchuan were not added to the raw material components, while the other steps and parameters are the same.

[0132] Test Example 1:

[0133] The experimental method is as follows:

[0134] 1) Take the hot filtrate (about 100°C) obtained in step (5) of Example 1, the extract obtained after extraction of Comparative Example 1 (about 78°C), and the mixture with added diatomaceous earth after extraction of Comparative Example 4 (about 78°C) as test samples.

[0135] 2) The dynamic viscosity of each sample at the process temperature was determined using a rotational viscometer. The sample was placed in a constant temperature water bath, and after the temperature stabilized, an appropriate rotor and rotation speed were selected to read the viscosity value (mPa·s) after the reading stabilized. For high-viscosity samples, the shear rate (rotation speed) was changed, and it was observed whether their rheological properties conformed to the characteristics of non-Newtonian fluids.

[0136] 3) Construct a laboratory plate and frame filter press simulation device with an effective filtration area of ​​0.01m². 2 The filter medium is polypropylene multifilament filter cloth (air permeability 600L / m²), which is consistent with the production line. 2 •s). Each group of samples was filtered under a constant pressure of 0.2 MPa, and the cumulative volume of the filtrate and the corresponding time were recorded until no filtrate flowed out or the predetermined time (30 min) was reached.

[0137] 4) Calculate the average filtration flux using the formula: J = V / (A × t), where V is the filtrate volume (L) and A is the filtration area (m²). 2 ), where t is the filtering time (h).

[0138] 5) After filtration, remove the filter cake, weigh it to determine its wet weight, and then dry it in a 105℃ oven until constant weight. Calculate the moisture content of the filter cake. The formula is: Moisture content = (Wet weight - Dry weight) / Wet weight × 100%.

[0139] The experimental results are shown in Table 1.

[0140] Table 1. Rheological parameters and filtration performance test data of each group of samples:

[0141] Group Dynamic viscosity (mPa·s, @60rpm) Shear thinning index (n value) <![CDATA[Average filtration flux (L / m 2 ·h)]]> Moisture content of filter cake (%) Example 1 4.2 0.98 245.6 32.4 Comparative Example 1 185.6 0.45 18.2 88.7 Comparative Example 4 12.8 0.92 85.3 55.1

[0142] According to the experimental data in Table 1, the dynamic viscosity of Comparative Example 1 reached as high as 185.6 mPa·s, and the rheological index n was 0.45, exhibiting typical pseudoplastic non-Newtonian fluid characteristics. This indicates that in the absence of competitive coordination with citric acid, the calcium ions released by oysters underwent a cross-linking reaction with the alginate in kelp, forming a high-viscosity "egg-box" calcium alginate gel network, significantly increasing the internal friction of the liquid phase. This gel structure directly led to a sharp drop in filtration flux to 18.2 L / m³. 2 The filter cake moisture content is close to 90%, indicating that the filter cake has high compressibility and viscosity, which can easily cause filter cloth blockage and material loss in industrial production.

[0143] In contrast, the viscosity of Example 1 was only 4.2 mPa·s, close to the rheological properties of water (n≈1), confirming that citrate successfully blocked the binding of calcium ions with alginic acid, and the system remained in a sol state without forming a gel blockage.

[0144] Further comparing Example 1 and Comparative Example 4, although Comparative Example 4 contained citric acid and had a lower viscosity (12.8 mPa·s), its filtration flux (85.3 L / m³) was significantly higher. 2 ·h) is only for Example 1 (245.6L / m 2 The moisture content of the filter cake was approximately one-third of that of the original (h), and the filter cake had a high moisture content. This indicates that relying solely on chemical blocking (anti-gelling) is insufficient. In Comparative Example 4, due to the lack of a 102°C thermal shock step, the calcium citrate in the system remained in a dissolved or amorphous particulate state, failing to utilize the reverse solubility characteristic to explosively generate crystals with a rigid structure. Example 1 precipitated a large number of micron-sized calcium citrate crystals through thermally induced phase change. These crystals, together with diatomaceous earth, constructed an incompressible rigid porous filter cake framework, which not only significantly improved the solid-liquid separation rate but also effectively reduced the adsorption and retention of the mother liquor by the filter cake, achieving a dual improvement in process efficiency and yield.

[0145] Test Example 2:

[0146] Experimental methods:

[0147] 1) Online sampling was performed during the preparation process of Example 1. Samples were collected immediately after extraction in step (3) (temperature 78°C) and at the end of the heat shock and maintenance of slight boiling for 15 minutes in step (4) (temperature 102°C). The 78°C sample was filtered through a 0.45μm filter membrane and the filtrate was recorded as sample A; the 102°C sample was rapidly filtered using a pressure filter equipped with a heating mantle (maintaining the filter temperature > 98°C) and the filtrate was recorded as sample B; another sample of the heat-shocked 102°C sample was naturally cooled to 50°C and then filtered, and the filtrate was recorded as sample C.

[0148] 2) Transfer 5.0 mL of the filtrate from each group of samples, add a nitric acid-perchloric acid mixture for microwave digestion, and after adjusting the volume, determine the free calcium ions (Ca) in the system using atomic absorption spectrophotometry (AAS). 2+ The concentration of ).

[0149] 3) Take the filtrate of each group of samples and determine the soluble total protein content using the Coomassie Brilliant Blue method to represent thermally unstable macromolecular impurities; at the same time, measure the transmittance (600nm) of each sample as an auxiliary indicator of the system's clarity.

[0150] 4) Using the measured value of sample A (78℃ extract) as a benchmark (100%), calculate the liquid phase retention rate of calcium ions and the removal rate of macromolecular impurities in samples B and C.

[0151] The experimental results are shown in Table 2.

[0152] Table 2. Correlation data between calcium ion phase transition and impurity removal at different temperature nodes:

[0153] Sampling Nodes / Operating Conditions System temperature (°C) <![CDATA[Liquid-phase Ca 2+ Concentration (mg / L)]]> <![CDATA[Liquid-phase Ca 2+ Retention rate (%)]]> Total protein concentration (μg / mL) Impurity removal rate (%) Light transmittance (%T) Sample A (extraction endpoint) 78 4256.3 100.0 (benchmark) 1245.8 0.0 (benchmark) 12.4 Sample B (heat shock and hot filtration) 102 682.4 16.03 158.2 87.3 94.6 Sample C (cooled and filtered) 50 4205.4 98.8 1108.5 11.0 19.8

[0154] According to the detection data in Table 2, the change in system temperature has a decisive influence on the concentration of calcium ions in the liquid phase and the impurity removal rate, and the two show a significant negative correlation.

[0155] During the extraction stage at 78℃ (sample A), liquid phase Ca 2+ The concentration was as high as 4256.3 mg / L, indicating that calcium citrate mainly existed in the form of dissolved or soluble complexes. The corresponding total protein concentration was 1245.8 μg / mL, and the transmittance was only 12.4%, indicating that a large number of high molecular weight impurities were suspended in the system.

[0156] When the temperature is rapidly increased to 102℃ and maintained at a slight boiling point (sample B), the liquid phase Ca... 2+ The concentration plummeted to 682.4 mg / L, with a retention rate of only 16.03%. This data confirms the thermodynamic characteristics of the reverse solubility of calcium citrate, namely, that high temperature induced a phase transition in approximately 84% of the dissolved calcium, resulting in the precipitation of a large number of solid crystals. Simultaneously, the impurity removal rate at this node jumped to 87.3%, and the transmittance improved to 94.6%. This synchronous change indicates that the precipitated calcium citrate microcrystals acted as highly efficient adsorbents in the system, capturing and co-precipitating large molecular impurities such as proteins that were originally in a dissolved or colloidal state through surface charge and specific surface area effects.

[0157] However, when the feed solution was cooled to 50°C and filtered (sample C), the liquid phase Ca 2+The concentration rebounded to 4205.4 mg / L (retention rate as high as 98.80%), while the impurity removal rate dropped to 11.0%. This data indicates that as the temperature decreased, the previously precipitated calcium citrate crystals underwent almost complete redissolution. Due to the disintegration of the crystal structure, impurities such as proteins that were originally locked in the crystal lattice or adsorbed on the surface were desorbed and released in large quantities, returning to the solution, leading to a further deterioration in transmittance. This result, conversely, supports the necessity of setting the process parameters of 102℃ heat shock combined with >95℃ heat filtration in this invention, proving that this scheme is not a simple physical filtration, but a dynamic physicochemical purification mechanism achieved by utilizing transient phase transitions.

[0158] Test Example 3:

[0159] The experimental method is as follows:

[0160] 1) Preparation of test solution: Accurately measure 10 mL of the final solution obtained in Examples 1-4 and Comparative Examples 1-6, place them in 25 mL volumetric flasks, dilute with methanol to the mark, shake well, centrifuge (12000 rpm, 10 min), and filter the supernatant through a 0.22 μm microporous membrane to obtain the test solution of each group.

[0161] 2) Preparation of reference solution: Weigh appropriate amounts of astragaloside A reference standard and cinnamaldehyde reference standard, add methanol to prepare a mixed solution containing 0.1 mg of astragaloside A and 0.05 mg of cinnamaldehyde per 1 mL, as the reference solution.

[0162] 3) Determination of Astragaloside A content (HPLC-ELSD method): High-performance liquid chromatography was used. The chromatographic column was an Agilent Zorbax SB-C18 (4.6 mm × 250 mm, 5 μm); the mobile phase was acetonitrile-water (32:68); the flow rate was 1 mL / min; the column temperature was 30℃; the drift tube temperature was 105℃; and the carrier gas flow rate was 2.5 L / min. The chromatogram was recorded, and the astragaloside A content was calculated.

[0163] 4) Cinnamaldehyde content determination (HPLC-UV method): High-performance liquid chromatography was used. The chromatographic column was the same as above; the mobile phase was acetonitrile-0.1% phosphoric acid solution (25:75); the detection wavelength was 290 nm; the flow rate was 1 mL / min; and the column temperature was 30℃. The chromatogram was recorded, and the cinnamaldehyde content was calculated.

[0164] 5) Total solids yield determination: Accurately measure 50 mL of each sample and place it in an evaporating dish that has been dried to constant weight. After evaporating to dryness in a water bath, dry it in an oven at 105℃ for 3 hours, transfer it to a desiccator to cool to room temperature, and weigh it.

[0165] 6) Data Calculation: Based on the amount of raw materials used and the background content of the raw materials as determined in the Chinese Pharmacopoeia, calculate the transfer rate of each indicator component and the total solids yield. Transfer rate (%) = (Total amount in the preparation / Total amount in the raw materials) × 100%.

[0166] The experimental results are shown in Table 3.

[0167] Table 3. Comparison of characteristic component transfer rate and solid yield under different process conditions:

[0168] Group Astragaloside A transfer rate (%) Cinnamaldehyde retention rate (%) Total solids yield (%) Example 1 88.42 82.15 23.6 Example 2 86.91 80.88 22.9 Example 3 89.05 83.42 24.1 Example 4 87.56 81.24 23.2 Comparative Example 1 (without citric acid) 41.33 76.5 11.8 Comparative Example 2 (No Oysters / Chemical Substitutes) 85.45 81.3 18.4 Comparative Example 3 (Cooling Filter) 86.12 80.95 26.8 Comparative Example 4 (No Heat Shock) 62.18 78.92 25.5 Comparative Example 5 (Acyclic Dextrin) 85.2 12.45 19.4 Comparative Example 6 (Flocculant) 58.74 75.3 15.9

[0169] According to the test results in Table 3, different process units have a significant and specific impact on the retention behavior of various chemical components.

[0170] Regarding the transfer rate of astragaloside A, Examples 1-4 maintained a high level of over 86%, while Comparative Example 1 only achieved 41.33%. This difference confirms the necessity of a competitive coordination mechanism. In Comparative Example 1, the gel network formed by calcium ions and alginic acid not only increased the viscosity of the liquid phase but also formed a dense diffusion-restricting layer at the solid-liquid interface, severely hindering the mass transfer process of this large molecular weight saponin, astragaloside A, from the internal tissue of the medicinal material to the solvent. Meanwhile, the data from Comparative Example 6 (58.74%) indicates that traditional polymeric flocculants (chitosan), while adsorbing impurities, also co-precipitate and remove some glycoside components through non-specific adsorption. In contrast, the calcium citrate microcrystals utilized in this invention exhibit a low adsorption affinity for astragaloside A, achieving selective purification.

[0171] Although the indicators of astragaloside A (85.45%) and cinnamaldehyde (81.30%) in Comparative Example 2 were similar to those in Example 1, indicating that chemically synthesized calcium citrate could also play a role in blocking gelation and assisting in clarification, its total solids yield was only 18.4%, significantly lower than the 23.6% in Example 1. This shows that in addition to providing calcium, oyster extract itself also contributes a large amount of water-soluble amino acids, trace elements, and collagen hydrolysates, and simple chemical reagent substitution cannot fully replicate the comprehensive medicinal value of the principal ingredient.

[0172] Comparative Example 3 showed a solids yield as high as 26.8%, even higher than Example 1. This high yield was mainly due to the retention of impurities through resolution. Since high-temperature hot filtration was not performed, the proteins, pectin, and other high-molecular-weight ineffective components that were originally adsorbed by the calcium citrate crystals were desorbed and released as the temperature decreased, remaining in the finished product. This demonstrates that the moderate yield of Example 1 represents a high-quality yield after removing impurities.

[0173] The same situation occurred in Comparative Example 4, where the total solids yield was as high as 25.5%, but the astragaloside transfer rate was only 62.18%. This indicates that at the conventional extraction temperature of 78°C, although astragaloside was dissolved from the medicinal material, due to the lack of a crystal phase transition step induced by 102°C, the calcium citrate and macromolecular impurities in the system remained in an amorphous colloidal or viscous semi-solid state, failing to form a rigid and porous filter aid framework. During filtration, this soft and viscous filter cake exhibited severe adsorption and encapsulation of macromolecular saponin components (such as astragaloside), leading to a decrease in the concentration of effective components in the filtrate. In contrast, Example 1 achieved a balance between efficient extraction and in-situ impurity removal using a high temperature of 102°C. The rigid filter cake constructed by the phase transition crystal reduced the adsorption of effective components, achieving a high transfer rate (88.42%) while controlling the yield at a reasonable 23.6%, thus improving the purity of the formulation.

[0174] Regarding volatile components, the cinnamaldehyde retention rate in Example 1 reached 82.15%, while in Comparative Example 5 it plummeted to 12.45%. This comparison quantifies the value of host-guest supramolecular inclusion. In Comparative Example 5, cinnamaldehyde, lacking the protection of the cyclodextrin cavity, experienced significant volatilization and hydrolysis losses during vacuum concentration and subsequent hot filtration. In contrast, Example 1, by forming a stable inclusion complex, locked the volatile molecules within the cavity, enabling it to withstand the high-temperature thermal shock operations in subsequent stages.

[0175] Taking all indicators into account, the rigid filter aid framework constructed by thermal phase change in Example 1 minimizes the adsorption and retention loss of effective substances in the filter cake while ensuring high transfer rate and filtrate clarity, and avoids the falsely high yield phenomenon caused by the redissolution of impurities in Comparative Example 3.

[0176] Test Example 4:

[0177] The experimental method is as follows:

[0178] 1) Take 500 mL of the final drug solution prepared in Examples 1-4 and Comparative Examples 3 and 6, and dispense them into colorless and transparent high borosilicate glass sample bottles and seal them.

[0179] 2) Use a turbidity meter to measure the initial turbidity value (T0) of each group of samples and record the data.

[0180] 3) Place a set of samples in a constant temperature and humidity chamber, set the temperature to 40℃±2℃ and the relative humidity to 75%±5%, and conduct an accelerated stability test, storing them statically for 30 days. Do not shake them during this period. After 30 days, take them out, gently turn them over and mix them (simulating transport oscillation), and measure the turbidity value (T30) again, and calculate the turbidity growth rate.

[0181] 4) Take another set of fresh samples, 50 mL each, and place them in centrifuge tubes. Centrifuge at 4000 rpm for 30 minutes using a high-speed refrigerated centrifuge. After centrifugation, carefully aspirate the supernatant, read the volume of the precipitate at the bottom of the centrifuge tube, and calculate the amount of precipitate formed (v / v% = precipitate volume / total volume × 100%).

[0182] The experimental results are shown in Table 4.

[0183] Table 4. Accelerated stability and centrifugal precipitation test data of the formulation:

[0184] Group Initial turbidity (NTU) Turbidity (NTU) after 30 days of accelerated treatment Turbidity growth rate (%) Centrifugal sediment volume (v / v%) Example 1 3.2 4.1 28.1 <0.05 (extremely small) Example 2 3.5 4.8 37.1 0.08 Example 3 2.9 3.6 24.1 <0.05 (extremely small) Example 4 3.4 4.5 32.3 0.1 Comparative Example 3 (Cooling Filter) 18.7 65.4 249.7 1.55 Comparative Example 6 (Traditional Flocculation) 8.4 22.1 163.1 0.68

[0185] According to the experimental data in Table 4, the thermodynamic path of the preparation process directly determines the physical stability of the final product.

[0186] The initial turbidity of Examples 1-4 was all below 4.0 NTU, and after a 30-day accelerated test at 40°C, the turbidity increase was minimal, and the amount of centrifuged sediment was extremely low (≤0.1%), indicating that the system was in a thermodynamically stable state. This confirms that the 102°C heat shock and 95°C hot filtration process route used in this invention effectively removes impurities (denatured proteins, calcium-pectin complexes) with low solubility at room temperature and prone to precipitation (at the high-temperature phase transition point) through microcrystalline adsorption and permanent removal with the filter cake. After cooling, the filtrate mainly contains highly water-soluble active ingredients and stable calcium citrate complexes, with no risk of supersaturated solute precipitation.

[0187] In contrast, Comparative Example 3 showed an initial turbidity of 18.7 NTU, which surged to 65.4 NTU after 30 days, with a precipitation amount of 1.55% (a clearly visible precipitate layer). This significant deterioration validates the reverse effect of the calcium citrate reverse solubility mechanism. When the feed solution was cooled to 50°C before filtration (Comparative Example 3), the calcium citrate crystals that precipitated at high temperatures underwent redissolution, releasing colloidal impurities trapped in the lattice or adsorbed on the surface back into the solution. Although these impurities temporarily dissolved or formed invisible microparticles at 50°C, during subsequent room temperature storage, as the system energy decreased and Brownian motion occurred, the microparticles gradually aggregated and bridged, eventually forming visible secondary precipitation and turbidity.

[0188] Furthermore, although the initial turbidity of Comparative Example 6 (traditional flocculation) was acceptable (8.4 NTU), the turbidity increased significantly after acceleration, with a centrifugal sedimentation amount of 0.68%. This indicates that the floc structure formed by the polymeric flocculant is relatively loose, and the excess flocculant or incompletely settled micro-flocs in the system are in a metastable state. Under long-term storage or shear force (centrifugation), they are prone to desorption or secondary aggregation, and their stability is far inferior to the subtractive purification system constructed by phase change crystals in the examples.

[0189] Test Example 5:

[0190] The experimental method is as follows:

[0191] 1) Select SPF grade mice, half male and half female, weighing 18-22g, and acclimatize them for 3 days.

[0192] 2) Under aseptic conditions, ascites fluid was extracted from S180 sarcoma mice and diluted with physiological saline to form a cell suspension (approximately 2 × 10⁻⁶). 7 S180 tumor-bearing mouse model was established by subcutaneous injection of 0.2 mL of the drug into the right axilla of each mouse (0.2 mL / mL).

[0193] 3) 24 hours after inoculation, the mice were randomly divided into 8 groups of 10 each: model control group, positive control group (cyclophosphamide), Example 1 group, comparative example 7 group (lacking Astragalus membranaceus), comparative example 8 group (lacking Laminaria japonica), comparative example 9 group (lacking Prunella vulgaris / Cat's Scratch), comparative example 10 group (lacking Platycodon grandiflorus), and comparative example 11 group (lacking Trogopterus xanthipes / Hemiptera japonica).

[0194] 4) Dosing regimen: Each treatment group was administered the drug once daily by gavage. The dosage was calculated based on the clinically intended human dosage and the conversion factor based on the mouse body surface area. The model control group was administered an equal volume of physiological saline by gavage. The positive control group was injected intraperitoneally with cyclophosphamide (20 mg / kg) every other day. The administration was continued for 14 days.

[0195] 5) One hour after the last administration, blood was collected from the mouse eyeballs and placed in heparin sodium anticoagulant tubes. A portion of whole blood was collected and the low shear rate (10s) was measured using an automated hemorheometer. -1 Whole blood viscosity was measured; the remaining blood was centrifuged to separate plasma, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) in the plasma were detected using an ELISA kit.

[0196] 6) Sacrifice the mice, remove the subcutaneous tumor, and measure the tumor weight. Calculate the tumor inhibition rate using the formula: Tumor inhibition rate = (Average tumor weight in the model group - Average tumor weight in the treatment group) / Average tumor weight in the model group × 100%.

[0197] The experimental results are shown in Table 5.

[0198] Table 5. Results of tumor weight, tumor inhibition rate, immune factors, and blood rheological parameters in mice of each group:

[0199] Group Average tumor weight (g) Tumor inhibition rate (%) TNF-α (pg / mL) IL-2 (pg / mL) Whole blood viscosity (mPa·s, 10s⁻¹) Model control group 1.68±0.24 - 12.45±3.1 8.32±1.5 9.85±0.82 Positive control group 0.54±0.11 67.86 15.60±2.8 10.15±1.9 8.92±0.65 Example 1 Group 0.65±0.13 61.31 38.42±5.2 24.56±3.4 6.12±0.44 Comparative group 7 (lacking Astragalus membranaceus) 1.02±0.18 39.29 16.85±2.9 11.20±2.1 7.05±0.58 Comparative example 8 groups (lacking kelp) 0.95±0.15 43.45 32.10±4.5 20.88±2.8 6.45±0.51 Comparative example: 9 groups (lacking summer / cat) 1.15±0.21 31.55 28.54±3.8 19.45±2.5 6.88±0.62 Comparative example 10 groups (lacking Platycodon grandiflorus) 1.08±0.19 35.71 30.12±4.1 21.05±3.0 6.95±0.55 Comparative Example 11 (Missing 5 stones / stones) 0.98±0.16 41.67 34.20±4.8 22.15±2.9 9.15±0.76

[0200] Based on the pharmacodynamic experimental data in Table 5, the complete formula combination in Example 1 exhibited the best overall therapeutic effect, with a tumor inhibition rate of 61.31%, and demonstrated multi-target synergistic advantages in immune regulation and microcirculation improvement. The data variation patterns of each missing ingredient ratio reveal the inherent logic of the principal, assistant, adjuvant, and guide formula of this invention:

[0201] First, the tumor inhibition rate of control group 7 (lacking Astragalus membranaceus) significantly decreased to 39.29%, and the levels of TNF-α and IL-2 were only slightly higher than those of the model group, far lower than those of Example 1. Astragalus membranaceus, as the principal herb, has its core active ingredient, Astragalus polysaccharide, which is an initiator of the body's immune surveillance system. The absence of Astragalus membranaceus directly leads to the body's inability to effectively mobilize endogenous cytokines to kill tumor cells, confirming the premise of supporting the body's resistance and eliminating pathogenic factors.

[0202] Secondly, the whole blood viscosity of Comparative Example 11 (lacking Trogopterus xanthipes / Hedyotis diffusa) was as high as 9.15 mPa·s, which was not statistically different from the model group (9.85 mPa·s) but significantly higher than that of Example 1 (6.12 mPa·s). Trogopterus xanthipes and Hedyotis diffusa, as adjuvants, play a crucial role in improving the microcirculation around the tumor due to their blood-activating and stasis-removing functions. If the stagnant microcirculation is not broken, not only will the body's immune cells have difficulty penetrating to the core of the lesion, but the distribution of exogenous drug components will also be hindered. Furthermore, the resinous components rich in these two herbs were effectively solubilized in this invention through cyclodextrin inclusion complexation technology. The decreased efficacy of Comparative Example 11 also indirectly verifies the necessity of inclusion complexation technology for exerting the activity of hydrophobic drugs.

[0203] Furthermore, the tumor inhibition rate was lowest (31.55%) in ratio 9 (lacking Prunella vulgaris / Cat's Scratch). These two herbs are direct eliminators of pathological products of phlegm-fire stagnation; their absence significantly weakened the compound's ability to directly ablate solid nodules.

[0204] Finally, the first example group not only showed a high tumor inhibition rate, but also did not exhibit the weight loss and immunosuppression common in the positive control group (cyclophosphamide) (although TNF-α was increased in the cyclophosphamide group, the overall condition was poor). This indicates that the traditional Chinese medicine composition of the present invention, while achieving the therapeutic effect of eliminating blood stasis and dissipating nodules, effectively avoids the drawback of excessive attacking and damaging the body's vital energy through the combination of Astragalus membranaceus, Ophiopogon japonicus and other drugs, thus realizing the clinical value of enhancing efficacy and reducing toxicity.

[0205] Test Example 6:

[0206] The experimental method is as follows:

[0207] 1) Select SPF grade C57BL / 6 mice, male, weighing 20-22g, and acclimatize them for 3 days.

[0208] 2) Establishment of a bleomycin (BLM)-induced pulmonary nodule (pulmonary fibrosis) model: Mice were anesthetized with isoflurane inhalation and fixed on a control table. Blemish-containing saline solution (2.5 mg / kg) was administered via endotracheal intubation and instilled into the trachea in a single instillation. Immediately after instillation, the mice were upright and rotated for approximately 1 minute to ensure even distribution of the drug in the lungs, inducing inflammatory exudation and collagen deposition to form nodular lesions. The blank control group received only an equal volume of sterile saline solution.

[0209] 3) The day after modeling, the surviving mice were randomly divided into 8 groups of 10 each: model control group, positive control group (pirfenidone), Example 1 group, comparative example 7 group (lacking Astragalus membranaceus), comparative example 8 group (lacking Laminaria japonica), comparative example 9 group (lacking Prunella vulgaris / Cat's Scratch), comparative example 10 group (lacking Platycodon grandiflorus), and comparative example 11 group (lacking Trogopterus xanthipes / Hemiptera japonica).

[0210] 4) Dosing regimen: Each treatment group was administered the drug once daily by gavage. The dosage was calculated based on the clinically intended human dosage and the conversion factor based on the mouse body surface area. The model control group and blank control group were administered an equal volume of physiological saline by gavage. The positive control group was administered pirfenidone solution (300 mg / kg) by gavage. The administration was continued for 28 days.

[0211] 5) One hour after the last administration, blood was collected from the eyeballs of mice to prepare serum. The levels of transforming growth factor-β1 (TGF-β1) and hyaluronic acid (HA) in the serum were detected by ELISA as indicators reflecting the activity of fibrotic nodules and matrix accumulation.

[0212] 6) Sacrifice the mice, completely dissect the lung tissue, rinse with cold physiological saline and dry, weigh the wet lung, and calculate the lung coefficient (lung coefficient = wet lung weight mg / body weight g); take the right lower lobe tissue and measure the hydroxyproline (HYP) content to quantitatively assess the degree of collagen deposition and hardening in the lung tissue (the material basis of nodules).

[0213] Left lung tissue was fixed, embedded, and sectioned. Masson trichrome staining was performed, and the tissue was observed under a microscope (×100x) and scored using the Ashcroft scale (0–8 points). The higher the score, the more severe the nodulation and fibrosis.

[0214] The experimental results are shown in Table 6.

[0215] Table 6. Results of lung coefficient, pathological score, and nodule-related biochemical indicators in each group of mice:

[0216] Group Lung coefficient (mg / g) Ashcroft pathology score (0–8 points) HYP content (μg / mg) TGF-β1 (pg / mL) HA (ng / mL) Blank control group 4.65±0.32 0.15±0.05 0.32±0.04 15.20±2.5 45.12±5.8 Model control group 9.82±0.85 6.45±0.62 1.15±0.12 148.50±15.4 185.60±18.2 Positive control group 6.15±0.52 2.85±0.35 0.58±0.06 62.40±8.5 88.45±9.6 Example 1 Group 5.85±0.48 2.42±0.28 0.51±0.05 55.10±7.2 76.20±8.1 Comparative group 7 (lacking Astragalus membranaceus) 8.25±0.72 5.10±0.55 0.92±0.09 112.40±12.1 145.20±14.5 Comparative example 8 groups (lacking kelp) 7.95±0.68 4.85±0.48 0.88±0.08 98.50±10.5 138.60±13.8 Comparative example: 9 groups (lacking summer / cat) 7.55±0.65 4.50±0.52 0.82±0.09 92.10±9.8 125.40±12.5 Comparative example 10 groups (lacking Platycodon grandiflorus) 7.20±0.61 4.10±0.45 0.75±0.07 85.20±8.9 112.50±11.2 Comparative Example 11 (Missing 5 stones / stones) 7.60±0.66 4.65±0.51 0.85±0.08 95.60±10.2 132.80±13.4

[0217] Based on the pharmacodynamic experimental data in Table 6, Example 1 demonstrated significant advantages in the intervention for pulmonary nodular lesions, with its improvement effects on lung coefficient, pathological score, and collagen deposition index (HYP) being superior to or close to those of the positive control drug pirfenidone. The differences in data from the various incomplete ingredient comparisons further corroborate the scientific validity of the Qi-tonifying, Yin-nourishing, and nodule-softening formulation strategy of this invention.

[0218] First, the comparative sample 7 (lacking Astragalus membranaceus) showed the closest correlation to the model group in various indicators, with a lung coefficient as high as 8.25 mg / g and a HYP content of 0.92 μg / mg. This indicates that without the qi-tonifying and stagnation-removing effects of the principal herb Astragalus membranaceus, the body is unable to expel the pathological products (phlegm) accumulated in the lungs through the normal qi-promoting action, leading to severe interstitial edema and massive collagen fiber deposition. This also verifies the traditional Chinese medicine theory that when the body's vital energy is abundant, pathogenic factors cannot invade, and that qi is the commander of blood, and that the smooth flow of qi eliminates phlegm. In other words, tonifying the body's vital energy is the foundation for treating pulmonary nodules.

[0219] Secondly, data from Comparative Example 8 (lacking kelp) and Comparative Example 9 (lacking Prunella vulgaris / Cat's Scratch Grass) showed that the levels of TGF-β1 and HA significantly increased after the absence of drugs for softening and dispersing nodules and clearing heat and resolving phlegm. These two groups of drugs directly target tangible phlegm and hard nodules; their absence makes it difficult for pulmonary nodules to soften and be absorbed, and the fibrosis process cannot be effectively curbed. In particular, the iodine and polysaccharide components abundant in kelp play a key role in inhibiting collagen synthesis in the nodule matrix.

[0220] Furthermore, the experimental results of Comparative Example 10 (lacking Platycodon grandiflorus) showed that its efficacy was significantly weaker than that of Example 1. Platycodon grandiflorus, as a catalytic agent, has the special effect of carrying medicine upwards and guiding it into the lungs. The absence of Platycodon grandiflorus makes it difficult for other effective components in the compound to accumulate in the lung lesions, thereby reducing the overall efficacy and confirming the importance of targeted drug delivery.

[0221] Finally, the high HYP content (0.85 μg / mg) in Comparative Example 11 (lacking Wulingzhi / Shijianchuan) suggests that the formation of pulmonary nodules is accompanied by microcirculatory disturbances (pulmonary vascular obstruction). The lack of blood-activating and stasis-removing drugs leads to obstruction of pulmonary vascular channels, and the combination of blood stasis and phlegm accelerates the transformation of granulomas into fibrotic nodules.

[0222] In summary, Example 1, through the organic combination of Astragalus membranaceus to invigorate Qi and strengthen the body, Laminaria japonica and Prunella vulgaris to soften hardness and resolve phlegm, Trogopterus xanthipes to invigorate blood and unblock collaterals, and Platycodon grandiflorus to guide the medicine into the lungs, blocked the pathological chain of phlegm and blood stasis from the source and significantly inhibited the formation and development of pulmonary nodules.

[0223] Test Example 7:

[0224] The experimental method is as follows:

[0225] 1) Select SPF-grade male SD rats, weighing 180-200g, and acclimatize them for 3 days.

[0226] 2) Construction of a lung injury model of Qi deficiency and blood stasis: A composite modeling method was used. First, rats were placed in cold water (0-4℃) for 5 minutes daily to deplete Yang Qi, for 7 consecutive days. Then, starting on the 8th day, rats were subcutaneously injected with epinephrine hydrochloride (0.8mg / kg) twice daily in their backs and placed in a smoke chamber to inhale cigarette smoke (30 minutes each time), for 14 consecutive days. This model simulates the pathological state of lung Qi deficiency and blood stasis caused by cold stimulation, emotional stress, and environmental pollution in clinical practice. The blank control group did not undergo the above modeling procedures.

[0227] 3) Grouping and administration: After successful modeling, rats that died or had extremely poor physical signs were removed, and the remaining rats were randomly divided into 8 groups of 10 each: model control group, positive control group (compound Danshen dripping pills), Example 1 group, comparative example 7 group (lacking Astragalus membranaceus), comparative example 8 group (lacking Laminaria japonica), comparative example 9 group (lacking Prunella vulgaris / Cat's Scratch Grass), comparative example 10 group (lacking Platycodon grandiflorus), and comparative example 11 group (lacking Trogopterus xanthipes / Schizonepeta tenuifolia).

[0228] 4) Dosing regimen: Each treatment group was administered the drug once daily by gavage, with the dosage calculated based on the clinically intended human dose and the conversion factor for rat body surface area; the model control group and blank control group were administered an equal volume of physiological saline by gavage; the positive control group was administered Compound Danshen Dripping Pills suspension (400 mg / kg) by gavage. Administration continued for 14 days.

[0229] 5) Detection Indicators: Blood was collected from the abdominal aorta of rats one hour after the last administration, and heparin was used for anticoagulation. Whole blood viscosity (high shear 200 / s, low shear 3 / s) and plasma viscosity (PV) were measured using a fully automated blood rheometer; fibrinogen (FIB) content was measured using a coagulation method; and platelet aggregation rate (PAgT, induced by ADP) was also measured. These indicators directly reflect the severity of blood stasis and microcirculatory disturbances in the body.

[0230] The experimental results are shown in Table 7.

[0231] Table 7. Results of blood rheology and coagulation function indices in each group of rats:

[0232] Group Whole blood viscosity at low shear rate (mPa·s) Whole blood viscosity at high shear rate (mPa·s) Plasma viscosity (mPa·s) Fibrinogen (g / L) Platelet aggregation rate (%) Blank control group 8.25±0.65 4.12±0.35 1.25±0.12 2.45±0.25 35.40±4.2 Model control group 22.45±2.15 7.85±0.68 2.15±0.18 5.82±0.55 78.50±6.8 Positive control group 12.10±1.20 4.95±0.45 1.45±0.14 3.10±0.32 45.20±5.1 Example 1 Group 10.85±1.05 4.62±0.42 1.38±0.13 2.85±0.28 41.10±4.8 Comparative group 7 (lacking Astragalus membranaceus) 17.55±1.65 6.45±0.58 1.75±0.16 4.25±0.42 62.40±5.9 Comparative example 8 groups (lacking kelp) 14.20±1.35 5.35±0.48 1.55±0.15 3.55±0.35 52.30±5.5 Comparative example 9 groups (lacking summer / cat) 13.80±1.25 5.25±0.46 1.52±0.15 3.40±0.33 50.10±5.2 Comparative example 10 groups (lacking Platycodon grandiflorus) 12.95±1.22 5.05±0.44 1.48±0.14 3.25±0.31 48.50±5.0 Comparative Example 11 (Missing 5 stones / stones) 19.80±1.85 6.95±0.62 1.95±0.17 4.95±0.48 68.20±6.2

[0233] Based on the experimental data analysis in Table 7, Example 1 showed significant efficacy in improving the hypercoagulable state and microcirculatory disturbances in rats with lung injury. Its ability to reduce whole blood viscosity, plasma viscosity, and inhibit platelet aggregation was superior to the positive control drug, Compound Danshen Dripping Pills. The differences in data from the various incomplete ingredient comparisons reveal the necessity of treating both qi and blood in the treatment of pulmonary nodules.

[0234] First, the data from Comparative Example 11 (lacking Trogopterus xanthipes / Scutellaria baicalensis) showed the worst performance, with a whole blood viscosity low-shear value as high as 19.80 mPa·s and a platelet aggregation rate as high as 68.20%. This result directly confirms the key role of blood-activating and stasis-removing drugs in the formulation. Trogopterus xanthipes and Scutellaria baicalensis directly disrupt the blood stasis environment on which nodules depend for survival by reducing fibrinogen levels and inhibiting platelet aggregation, preventing the formation of microthrombi and opening up microcirculation channels for other drugs to enter the lesion.

[0235] Secondly, the results of Comparative Example 7 (lacking Astragalus membranaceus) are highly valuable for further investigation. Although the blood-activating herbs were retained, the absence of Astragalus membranaceus, the principal herb, resulted in significantly higher rheological parameters (such as whole blood viscosity of 17.55 mPa·s) compared to Example 1. This verifies the traditional Chinese medicine theory that Qi is the commander of blood, and that blood flows when Qi flows. In a state of Qi deficiency, blood is weakly propelled, and even with the use of blood-activating herbs, it is difficult to fundamentally reverse the stagnant state of blood. Astragalus membranaceus, by tonifying Qi and raising Yang, enhances cardiac output and vascular tone, thereby achieving a synergistic effect of invigorating Qi to promote blood circulation.

[0236] Furthermore, data from comparative example 8 (lacking kelp) and comparative example 9 (lacking prunella vulgaris / cat's claw grass) showed that the absence of expectorant and phlegm-resolving drugs also led to an increase in blood viscosity. This suggests a pathological symbiotic relationship between phlegm and blood stasis, namely, phlegm obstructing blood vessels leads to blood stasis. Kelp and other drugs, by regulating lipid metabolism and reducing inflammatory exudation (lowering plasma viscosity), reduce tangible deposits in the blood, thereby helping to improve blood rheology.

[0237] Finally, although the data of Comparative Example 10 (lacking Platycodon grandiflorus) was better than the other comparative examples, it was still not as good as Example 1. This shows that Platycodon grandiflorus's function of promoting lung qi helps to regulate the rise and fall of qi in the lungs, thereby assisting the circulation of qi and blood throughout the body and avoiding blood stasis caused by local qi stagnation.

[0238] In summary, Example 1, through the synergistic effects of Astragalus membranaceus in tonifying qi and promoting blood circulation, Trogopterus xanthipes and Hedyotis diffusa in breaking up blood stasis and removing blood stasis, and Laminaria japonica and Prunella vulgaris in resolving phlegm and unblocking the meridians, comprehensively improved the body's hemorheological state, created a good microcirculatory environment for eliminating pulmonary nodules, and fundamentally blocked the pathological process of blood stasis and nodule formation.

[0239] Test Example 8:

[0240] The experimental steps are as follows:

[0241] 1) Select SPF grade C57BL / 6 mice, male, weighing 20-22g, and acclimatize them for 3 days.

[0242] 2) Construction of a lipopolysaccharide (LPS)-induced acute inflammatory injury model of the lungs: This model can simulate the severe inflammatory response environment during the acute exacerbation of pulmonary nodules or the early stage of nodule formation. Mice were anesthetized and the model was established by intratracheal infusion of LPS (5 mg / kg). The blank control group was infused with an equal volume of sterile saline.

[0243] 3) Grouping and administration: Prophylactic administration for 3 days before modeling and therapeutic administration for 3 days after modeling, for a total of 6 days. Mice were randomly divided into 8 groups, with 10 mice in each group: model control group, positive control group (dexamethasone), Example 1 group, comparative example 7 group (lacking Astragalus membranaceus), comparative example 8 group (lacking Laminaria japonica), comparative example 9 group (lacking Prunella vulgaris / Cat's Scratch), comparative example 10 group (lacking Platycodon grandiflorus), and comparative example 11 group (lacking Trogopterus xanthipes / Hedyotis diffusa).

[0244] 4) Dosing regimen: Each treatment group was administered the drug once daily by gavage; the model control group and the blank control group were administered an equal volume of physiological saline by gavage; the positive control group was injected intraperitoneally with dexamethasone sodium phosphate injection (5 mg / kg) as a control for potent anti-inflammatory effects.

[0245] 5) Detection indicators: 24 hours after the last administration, mice were sacrificed and bronchoalveolar lavage (BAL) was performed. BAL was collected, centrifuged, and the precipitate was stained with Wright-Giemsa to calculate the total white blood cell count and neutrophil percentage (reflecting the degree of inflammatory infiltration). The supernatant was collected, and the concentrations of pro-inflammatory cytokines TNF-α (tumor necrosis factor-α), IL-6 (interleukin-6), and IL-1β (interleukin-1β) were detected by ELISA.

[0246] The experimental results are shown in Table 8.

[0247] Table 8. Results of inflammatory cell count and inflammatory factor detection in BALF of mice in each group:

[0248] Group <![CDATA[Total white blood cell count (×10 5 / mL)]]> Neutrophil percentage (%) TNF-α (pg / mL) IL-6 (pg / mL) IL-1β (pg / mL) Blank control group 1.12±0.15 3.50±1.2 18.50±2.5 25.40±3.2 12.80±1.5 Model control group 15.85±1.45 68.45±5.8 285.60±22.4 310.50±25.6 145.20±12.8 Positive control group 4.25±0.42 15.60±2.5 65.40±6.8 78.50±7.5 35.60±3.8 Example 1 Group 4.85±0.48 18.25±2.8 72.10±7.2 85.20±8.1 39.50±4.2 Comparative group 7 (lacking Astragalus membranaceus) 8.95±0.85 35.40±4.2 145.20±14.5 165.40±15.2 78.50±7.5 Comparative example 8 groups (lacking kelp) 9.45±0.92 38.60±4.5 158.60±16.2 175.20±16.8 85.40±8.2 Comparative example: 9 groups (lacking summer / cat) 11.20±1.15 45.20±5.2 195.40±18.5 215.60±20.5 98.60±9.4 Comparative example 10 groups (lacking Platycodon grandiflorus) 7.50±0.72 28.50±3.5 115.80±11.2 135.40±12.5 62.40±6.5 Comparative Example 11 (Missing 5 stones / stones) 7.85±0.76 29.80±3.6 122.50±12.8 142.50±13.6 65.80±6.8

[0249] Based on the experimental data analysis in Table 8, Example 1 demonstrated excellent performance in inhibiting excessive pulmonary immune responses and clearing inflammatory factors. Its anti-inflammatory effect was close to that of the potent steroid drug dexamethasone, but without the potential immunosuppressive side effects of steroid drugs. The differences in data from the various incomplete ingredient comparison ratios further validated the scientific connotation of the present invention's heat-clearing, detoxifying, and pathogen-eliminating formula.

[0250] First, the data from Comparative Example 9 (lacking Prunella vulgaris / Nepeta catata) were the most significant, with significantly higher levels of TNF-α (195.40 pg / mL) and IL-6 in BALF compared to Example 1. In Traditional Chinese Medicine, Prunella vulgaris and Nepeta catata primarily enter the liver and lung meridians, possessing strong heat-clearing, detoxifying, swelling-reducing, and nodule-dispersing effects. The absence of these two herbs resulted in the inability to clear heat toxins from the lungs, leading to persistently high expression of inflammatory mediators and providing a volatile environment for the formation and maintenance of nodules. This confirms that heat-clearing and detoxifying herbs are key to blocking the inflammatory progression of nodules.

[0251] Secondly, the high percentage of neutrophils (38.60%) and the level of inflammatory factors in ratio 8 (lacking kelp) suggest that kelp not only softens hardened masses, but its expectorant effect also includes a mechanism of inhibiting inflammatory exudation. Phlegm-heat congealing is the root cause of the difficulty in treating pulmonary nodules. Without kelp, phlegm cannot be resolved, further encapsulating heat toxins, making it difficult for inflammation to subside.

[0252] Furthermore, the results of Comparative Example 7 (lacking Astragalus) (TNF-α 145.20 pg / mL) revealed the bidirectional nature of immune regulation. Although the main function of Astragalus is to tonify Qi, Qi deficiency weakens the body's defensive Qi, making it unable to effectively resist external pathogens (such as LPS) and unable to clear pathological products through normal immune recognition. Without Astragalus, the body exhibits a state of "deficiency of vital Qi and lingering pathogenic factors," leading to persistent inflammation. The excellent performance of Example 1 demonstrates that Astragalus achieves its anti-inflammatory effect by strengthening the body's resistance.

[0253] Finally, Comparative Example 10 (lacking Platycodon grandiflorus) further confirmed the importance of its guiding role. Without Platycodon grandiflorus, the drug could not accumulate at high concentrations on the alveolar surface, leading to a decreased ability to clear local inflammatory factors in BALF.

[0254] In summary, Example 1 constructs a multi-layered anti-inflammatory defense by directly suppressing the fire with Prunella vulgaris and Cat's Claw Grass, resolving phlegm and reducing fire with Laminaria japonica, strengthening the body's resistance with Astragalus membranaceus, and delivering the medicine directly to the affected area with Platycodon grandiflorus. This formula not only physically softens nodules (as shown in Test Example 6), but also improves the lung microenvironment at the biochemical level, eliminating the inflammatory driving force that induces nodule formation.

[0255] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A traditional Chinese medicine composition for invigorating qi, nourishing yin, supporting the body's resistance, and resolving stagnation and masses, characterized in that, Made from the following ingredients in parts by weight: Astragalus membranaceus 300-600 parts, Oyster shell 250-350 parts, Laminaria japonica 150-250 parts, Prunella vulgaris 150-250 parts, Cat's claw grass 150-250 parts, Hedyotis diffusa 150-200 parts, Spatholobus suberectus 200-300 parts, Forsythia suspensa 100-150 parts, Ophiopogon japonicus 100-150 parts, Coix lacryma-jobi 200-300 parts, Cinnamomum cassia 50-70 parts, Trogopterus xanthipes 100-140 parts, Citrus reticulata 70-90 parts, Platycodon grandiflorus 60-100 parts, Zingiber officinale 30-50 parts, Citrus aurantium 70-90 parts.

2. The traditional Chinese medicine composition for invigorating qi, nourishing yin, supporting the body's resistance, and resolving stagnation and masses according to claim 1, characterized in that, The weight parts of the raw materials are: Astragalus membranaceus 450 parts, Oyster shell 300 parts, Laminaria japonica 200 parts, Prunella vulgaris 200 parts, Cat's claw grass 200 parts, Hedyotis diffusa 180 parts, Spatholobus suberectus 250 parts, Forsythia suspensa 120 parts, Ophiopogon japonicus 120 parts, Coix lacryma-jobi 250 parts, Cinnamomum cassia 60 parts, Trogopterus xanthipes 120 parts, Citrus reticulata peel 80 parts, Platycodon grandiflorus 80 parts, Zingiber officinale 40 parts, Citrus aurantium 80 parts.

3. The traditional Chinese medicine composition for invigorating qi, nourishing yin, supporting the body's resistance, and resolving stagnation and masses according to claim 1, characterized in that, The raw materials also contain pharmaceutically acceptable excipients, which include at least anhydrous citric acid and hydroxypropyl-β-cyclodextrin.

4. The traditional Chinese medicine composition for invigorating qi, nourishing yin, supporting the body's resistance, and resolving stagnation and masses according to claim 3, characterized in that, The amount of anhydrous citric acid used is 0.7 to 1.2 times the weight of the oyster; the amount of hydroxypropyl-β-cyclodextrin used is 0.1 to 0.4 times the total weight of cinnamon twig, dried tangerine peel, ginger, five-spice powder, immature bitter orange, rock hemp, and ginger.

5. The traditional Chinese medicine composition for invigorating qi, nourishing yin, supporting the body's resistance, and resolving stagnation and masses according to claim 1, characterized in that, The traditional Chinese medicine composition is an oral liquid, compound preparation, or syrup.

6. A method for preparing a traditional Chinese medicine composition according to any one of claims 1-5 that invigorates qi, nourishes yin, strengthens the body, dissipates blood stasis, and resolves masses, characterized in that, Includes the following steps: S1. Preparation of supramolecular inclusion complex suspension of lipophilic components: Cinnamon twig, tangerine peel, ginger, five-spice powder, bitter orange peel, and rock hemp seed were extracted with alcohol. Cyclodextrin solution was added to the extract for inclusion, and the ethanol was recovered to obtain the inclusion complex suspension. S2. Preparation of calcium citrate precursor reaction solution: Oysters are crushed and mixed with water, citric acid is added, and the mixture is reacted under heating conditions. The pH value is adjusted to obtain a precursor reaction solution containing calcium citrate microcrystals and calcium hydrogen citrate. S3, Blocking Extraction: The precursor reaction solution obtained in S2 is used as the extraction solvent, and the remaining hydrophilic medicinal components are added for extraction at 75-80℃; S4. Thermal phase change and filtration: After extraction, the temperature of the liquid is rapidly raised to 100-103℃ and maintained at a slight boiling state to induce the precipitation of calcium citrate crystals; then a filter aid is added, and filtration is carried out under the condition that the temperature of the liquid is higher than 90℃, and the hot filtrate is collected. S5. Mixing: Combine the inclusion complex suspension obtained in S1 with the hot filtrate obtained in S4, and adjust the pH value to obtain the final product.

7. The preparation method according to claim 6, characterized in that, In step S1, the specific operation of the encapsulation is as follows: Hydroxypropyl-β-cyclodextrin aqueous solution was added directly to the alcohol extract to adjust the volume fraction of ethanol in the system to 30-40%. The temperature was lowered to 40-50℃, and the mixture was sheared at 2000-3000 rpm for 20-30 minutes using a high-shear homogenizer.

8. The preparation method according to claim 6, characterized in that, In step S2, the specific preparation operation is as follows: Add oysters to water, add anhydrous citric acid, heat to 70-80℃, stir and react at a constant temperature for 30-50 minutes, and adjust the pH of the system to 4.2-4.8 after the reaction is completed; wherein, the weight ratio of anhydrous citric acid to oysters is (0.7-1.13):

1.

9. The preparation method according to claim 6, characterized in that, In step S4, the condition for the thermally excited phase transition is: The liquid material is heated to 102-103°C at a heating rate of 2.5°C / min or higher, and maintained under micro-pressure for 10-20 minutes. The filtering operation is as follows: At the end of the boiling process, add 0.5% to 1.0% of the volume of the liquid to the vessel, stir evenly, and pump the liquid into the preheated filtration equipment while it is still hot, controlling the temperature of the filtration medium to be no lower than 95°C. In step S5, adjusting the pH value involves adding sodium carbonate solution to adjust the pH value to 6.0-7.

0.

10. The use of the traditional Chinese medicine composition according to any one of claims 1-5 in the preparation of a medicine for treating pulmonary nodules, thyroid nodules, breast nodules, scrofula or phlegm nodules caused by deficiency of both qi and yin and phlegm and blood stasis.