Compound medicine for inheriting cough and asthma and preparation method thereof

Abstract

The invention discloses an inherited cough and asthma relieving compound medicine and a preparation method thereof. The medicine is prepared into various dosage forms such as granules, tablets and the like from 14 traditional Chinese medicines such as honey-fried ephedra, semen armeniacae amarae, lumbricus and the like through the processes of superfine grinding, gradient decoction, low-temperature drying and the like. The innovation points are as follows: (1) ephedra-earthworm synergistically relieve spasm, stiff silkworm-schisandra chinensis jointly regulate and control a calcium ion channel, and rapid cough relieving and long-acting asthma relieving are realized; (2) gradient decoction is combined with an inclusion technology, so that the dissolution rate of ephedrine is increased by 42%, and the retention rate of glycyrrhizic acid is greater than or equal to 78%; (3) an IL-6 / TNF-alpha inflammation pathway is inhibited at multiple targets, and the airway hyperreactivity is reduced; and (4) the granule D90 is less than or equal to 150 microns, the water content is less than or equal to 5%, and the dissolution rate reaches 90% or above. Clinical tests show that the total effective rate is 91.7%, the FEV1 improvement rate is improved by 41.7% compared with that of a single-formula control group, and the hormone dosage can be reduced by 30%. The preparation has the advantages of traditional cough treatment experience and modern pharmaceutical technology, and provides a safe and effective new choice for treatment of CVA.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine compound for relieving cough and asthma and its preparation method, specifically to a Chinese medicine composition for treating cough variant asthma prepared based on traditional Chinese medicine theory and combined with modern pharmaceutical technology. Background Technology

[0002] Cough variant asthma (CVA), a specific subtype of bronchial asthma, is clinically characterized primarily by chronic dry cough, accompanied by pathological changes such as airway hyperresponsiveness, chronic inflammation, and airway remodeling. Epidemiological data shows that CVA accounts for 30%-40% of chronic cough cases, and approximately 30% of patients eventually develop typical asthma. Current mainstream treatment relies on inhaled corticosteroids (ICS) combined with long-acting β2-adrenergic agonists (LABAs), but long-term use can easily lead to systemic adverse reactions such as oral candidiasis and osteoporosis, and approximately 20% of patients do not respond well to ICS treatment. Traditional Chinese medicine has unique advantages in the treatment of chronic cough and asthma; however, existing cough-suppressing formulas are mostly designed for externally contracted coughs, and face three major bottlenecks in treating refractory CVA:

[0003] Firstly, the formulation lacks targeted targeting. Traditional cough remedies often focus on expectorant and antitussive (such as Er Chen Tang) and qi-regulating and asthma-relieving (such as Su Zi Jiang Qi Tang), but they are insufficient in regulating the airway neurogenic inflammation unique to CVA. Modern pharmacological studies have shown that CVA patients have significantly elevated levels of substance P and nerve growth factor (NGF) in their induced sputum, while existing formulas lack traditional Chinese medicine components that specifically regulate the neuroimmune network.

[0004] Secondly, the standardization of the preparation process is low. Most classic prescriptions still use the traditional dosage form of "decoction in water", which has problems such as low bioavailability and poor stability of active ingredients. Taking ephedra as an example, the water solubility of its active ingredient ephedrine is only 0.12%, and only 23% of the active ingredient is retained by conventional decoction, which directly affects the antispasmodic and antiasthmatic effects.

[0005] Third, the quality control system is inadequate. Current quality standards mostly rely on single indicator components (such as glycyrrhizic acid and flavonoids), making it difficult to comprehensively reflect the overall efficacy of the compound. Studies have shown that the combination of ephedra and earthworm in Suhuang Zhike Decoction has a significant synergistic effect, but current quality control methods cannot characterize this dynamic interaction.

[0006] To address the aforementioned issues, there is an urgent need to develop traditional Chinese medicine compound prescriptions based on modern pharmacology. By optimizing the composition and formulation, innovating the preparation process, and establishing a multi-dimensional quality control system, precise treatment of CVA can be achieved. Summary of the Invention

[0007] The purpose of this invention is to provide a traditional cough-relieving and asthma-suppressing compound medicine and its preparation method. This invention proposes a traditional cough-relieving and asthma-suppressing compound medicine and its preparation method. The traditional cough-relieving and asthma-suppressing compound medicine described in this patent is composed of processed ephedra, bitter almond, raw licorice root, platycodon root, burdock seed, cicada slough, silkworm, earthworm, coltsfoot flower, aster root, loquat leaf, schisandra fruit, pear peel, and honey. Among them, processed ephedra is pungent and warm, dispersing and relieving asthma; its ephedrine component can selectively stimulate β2-adrenergic receptors and relax bronchial smooth muscle. Bitter almond is bitter and descending, rich in amygdalin, and exerts an antitussive effect by inhibiting the cough center. Raw licorice root is neutral and sweet, harmonizing the various medicines and possessing anti-inflammatory and analgesic effects; its glycyrrhizic acid component can inhibit the release of inflammatory mediators. Platycodon grandiflorus promotes lung function and soothes the throat; its saponins promote the secretion and expulsion of respiratory mucus. Arctium lappa disperses wind-heat, and its arctiin has antiviral and immunomodulatory functions. Cicada slough gently clears heat, and Bombyx mori dispels wind and resolves phlegm; the combination of these two herbs can alleviate airway hyperresponsiveness. Earthworm is salty and cold, unblocking the meridians; it contains lumbrokinase and other components that can relax bronchial smooth muscle. Coltsfoot flower moistens the lungs and lowers qi, while Aster tataricus warms the lungs and resolves phlegm; the two work synergistically to enhance the antitussive effect. Loquat leaf clears the lungs and relieves adverse qi flow, while Schisandra chinensis astringes the lungs and nourishes the kidneys, together achieving the effect of relieving cough and asthma. Pear peel clears heat and moistens dryness, while honey nourishes the middle and moistens the lungs, acting as a flavoring agent and binder. The entire formula combines the elimination of pathogens with the support of the body's resistance, targeting cough caused by exogenous wind-cold and regulating the deficiency of the lungs, spleen, and kidneys, forming a complete system that treats both the symptoms and the root cause.

[0008] Furthermore, the drug preparation method employs a stepwise extraction and mixing process: First, ephedra, earthworm, and silkworm are subjected to ultra-fine pulverization to achieve a particle size of over 100 mesh. This step significantly increases the specific surface area of ​​the medicinal materials, promoting the rapid dissolution of active ingredients. Then, the remaining eleven medicinal materials are placed in a multi-functional extraction tank, and eight times the amount of drinking water is added initially. After heating to boiling, the mixture is continuously decocted for 2 hours. The high-temperature and high-pressure environment during this stage helps to break down plant cell walls, promoting the full release of water-soluble components such as flavonoids and alkaloids. For the second decoction, six times the amount of water is added, and a gentle decoction is maintained for 1.5 hours to further extract residual active substances. The two decoctions are combined, and impurities are removed by centrifugation. The liquid is then concentrated to a clear extract with a relative density of 1.10-1.15 at 60°C using a vacuum concentration device. This temperature range effectively removes moisture while maximizing the retention of heat-sensitive components. The previously prepared fine powder and clear extract are then mixed evenly in a specific ratio and placed in a vacuum drying oven at 60°C for low-temperature drying to avoid loss of volatile components due to high temperatures. Finally, the dried mixture is processed using a wet granulation process, with an appropriate amount of honey added as a binder. After granulation using a gyratory granulator, it undergoes secondary drying in a fluidized bed dryer to ensure that the moisture content of the granules is below 5%. This preparation process, through precise control of process parameters, achieves the synergistic extraction and efficient utilization of volatile, water-soluble, and fat-soluble components in the compound.

[0009] Furthermore, the decoction process employs a gradient water addition and differentiated decoction time design: the water addition for the first decoction is set at 8 times the total weight of the medicinal materials, based on research data on the water absorption characteristics of Chinese medicinal materials and the dissolution kinetics of active ingredients. Experimental verification shows that when the water addition reaches 8 times, the initial dissolution rate of polar components such as ephedrine in ephedra and amygdalin in apricot kernels reaches its maximum, and the cumulative release of active ingredients during subsequent decoctions shows a linear increasing trend over time. Continuous decoction for 2 hours ensures uniform temperature distribution within the medicinal materials, promotes osmotic pressure balance between intracellular and extracellular solutions, and allows the active ingredients to fully diffuse into the decoction. The water addition for the second decoction is adjusted to 6 times, based on the consideration that the tissue structure of the medicinal materials has been disrupted after the first decoction, thus improving subsequent extraction efficiency. Shortening the decoction time to 1.5 hours avoids the degradation of small molecule components due to prolonged high temperatures and increases the concentration of the decoction through the concentration process, laying the foundation for subsequent granulation. The organic combination of the two decoctions achieves efficient extraction and rational distribution of active ingredients.

[0010] Furthermore, the drug dosage form design fully considers patient convenience and clinical applicability: Granules utilize fluidized bed granulation technology, using spray drying to form free-flowing spherical granules from mixed powders, facilitating packaging and transportation while allowing for rapid disintegration and absorption when dissolved in warm water. Tablets employ double-layer compression technology, with an outer immediate-release layer containing fast-acting ingredients such as ephedra and licorice, and an inner sustained-release layer containing long-acting ingredients such as earthworm and schisandra, maintaining stable blood drug concentrations. Capsules use enteric coating materials, allowing the drug to bypass the gastric acid environment and be released directly into the intestines, making them particularly suitable for patients with weak spleen and stomach that are easily irritated. Oral liquid preparations utilize high-speed centrifugation and membrane filtration technology to remove large molecular impurities, and are combined with stevioside flavoring agents, making them especially suitable for children and people with swallowing difficulties. The development of multiple dosage forms meets the personalized needs of different patients and improves medication adherence.

[0011] Furthermore, the drug's mechanism of action focuses on the regulation of inflammatory cytokine networks: in vitro cell experiments revealed that earthworm extract significantly inhibited lipopolysaccharide (LPS)-induced IL-6 secretion from macrophages, and its mechanism of action may be related to the regulation of the NF-κB signaling pathway. The silkworm extract effectively downregulated TNF-α gene expression, alleviating airway inflammation. Animal model validation showed that after 7 days of continuous administration, serum IL-6 levels in model animals decreased by 42%, and TNF-α concentration in bronchoalveolar lavage fluid decreased by 38%. This dual regulatory effect not only alleviates acute inflammatory responses but also improves chronic airway inflammation by regulating the Th17 / Treg cell balance, providing a novel therapeutic target for cough-variant asthma.

[0012] Furthermore, the drug reduces intracellular calcium ion concentration in bronchial smooth muscle cells through multiple pathways: electrophysiological experiments show that schisandrin B in the formula can block L-type calcium channels, reducing the influx of calcium from outside the body; silkworm extract inhibits ryanodine receptor-mediated calcium release; and ephedrine promotes calcium ion efflux by activating β2 receptors. The synergistic effect of these three components reduces intracellular calcium ion concentration by 56%, significantly weakening smooth muscle contractility. In vitro tracheal strip experiments show that the tracheal rings dilate by 72% after drug action, with the effect lasting up to 6 hours. This calcium regulation mechanism provides a rapid and effective solution for relieving acute asthma attacks, while reducing dependence on β-receptor agonists.

[0013] Furthermore, the combined medication regimen embodies the concept of integrating traditional Chinese and Western medicine: Clinical trial data shows that when this formula is used in combination with inhaled corticosteroids, the daily dose of prednisolone can be reduced by 30% without compromising efficacy, thanks to the positive regulatory effect of glycyrrhizic acid on corticosteroid receptors. When used in combination with salbutamol, the bronchodilatory effects of the two drugs are additive, and the FEV1 improvement rate is 28% higher than that of the Western medicine monotherapy group. This regimen combines traditional Chinese medicine to regulate the body's constitution with Western medicine to quickly control symptoms, reducing the risk of side effects from long-term use of hormones and improving patient treatment compliance, providing a new approach to hierarchical medical treatment.

[0014] Furthermore, the quality control indicators for granules ensure product uniformity: A laser particle size analyzer is used to determine particle size distribution, requiring D90 ≤ 150 μm to ensure moderate particle size for easy swallowing, and D10 ≥ 20 μm to avoid excessively fine particles that may absorb moisture and clump. A dynamic moisture adsorption analyzer is used to detect moisture content, strictly controlling it below 5% to prevent deliquescence and deterioration during storage. Dissolution testing uses the paddle method, requiring the main component to dissolve at least 85% within 30 minutes. Heavy metal residue testing is conducted according to the Chinese Pharmacopoeia standards, with the content of harmful elements such as lead, cadmium, and arsenic all below one-third of the limit value. These stringent physicochemical indicators guarantee the safety, stability, and bioavailability of the formulation.

[0015] Furthermore, a dual-assurance system for quality control was established: Amygdalin content was determined using HPLC-DAD with an acetonitrile-0.1% phosphoric acid gradient elution as the mobile phase, a detection wavelength of 207 nm, and a requirement of ≥0.8 mg / g to ensure the compliance of the effective antitussive component. Glycyrrhizic acid ammonium salt content was determined using an ELSD detector, with evaporative light scattering detection conditions of a drift tube temperature of 105℃ and a nitrogen flow rate of 2.5 L / min, achieving a content ≥0.5 mg / g to characterize the stability of the anti-inflammatory component. Fingerprint analysis employed UPLC-QTOF-MS technology, matching 12 common peaks with a similarity ≥0.98 to comprehensively control the consistency of the compound chemical components. Microbial limit testing followed the general rules of the fourth part of the Chinese Pharmacopoeia, with a total aerobic bacterial count ≤1000 CFU / g, mold and yeast ≤100 CFU / g, and pathogenic bacteria not detectable. This multi-level quality control system ensures full traceability of the product from raw materials to finished product.

[0016] The beneficial effects of this invention are:

[0017] This formula is based on the principles of "dispelling wind and clearing the lungs, relieving spasms, stopping cough and soothing the throat," creatively integrating three classes of drugs: peripheral antitussive components: bitter almond (amygdalin) and loquat leaf (ursolic acid) exert antitussive effects by inhibiting the medullary cough center; anti-inflammatory and bronchodilator components: earthworm (lumbrokinase) and silkworm (ammonium oxalate) regulate the Th17 / Treg balance and inhibit the IL-17 / IL-23 inflammatory axis; mucosal repair components: coltsfoot flower (codorhizol) and aster (asterone) promote airway epithelial cell repair and reduce airway hyperresponsiveness. Network pharmacology predicts that this formula can act on 12 key targets and regulate multiple signaling pathways such as MAPK and NF-κB.

[0018] A gradient extraction process is used to achieve precise controlled release of components: ephedra, earthworm, and silkworm are ultra-finely pulverized (D90<15μm) to ensure rapid onset of action of ephedrine and hypoxanthine; the compound water extract (containing chlorogenic acid, glycyrrhetinic acid, etc.) is released slowly through inclusion technology to maintain blood drug concentration for 8 hours; honey binder forms a pH-responsive gel framework, which allows the drug to dissolve slowly in the low pH environment of the stomach, reducing gastrointestinal irritation.

[0019] Three key technological breakthroughs were achieved: microwave-assisted extraction increased the extraction rate of flavonoids by 42%; macroporous resin purification technology enriched the effective components (total flavonoids ≥35%, alkaloids ≥12%); and solid dispersion technology increased the solubility of poorly soluble components by 8-10 times. Pharmacokinetic studies showed that the time to peak plasma concentration of the main active ingredient was shortened by 40%, and bioavailability was increased by 2.3 times compared to traditional decoctions.

[0020] The optimal ratio was determined through orthogonal experiments: Ephedra:Earthworm = 3:5 resulted in the strongest β2 receptor agonist effect; Apricot kernel:Licorice = 1:0.6 achieved the peak antitussive synergistic index; Schisandra chinensis:Loquat leaf = 1:1 showed the best anticholinergic effect. Clinical trials showed that the FEV1 improvement rate was 41.7% higher with this ratio compared to the single-drug control group.

[0021] In vitro experiments have confirmed that the ephedrine + earthworm protease complex can reduce the intracellular calcium ion concentration in airway smooth muscle cells (EC). 50 =2.8 μg / mL); the glycyrrhizic acid + quercetin complex inhibited NF-κB nuclear translocation efficiency by 73%; the schisandrin A + asterone combination upregulated β2 receptor expression by 2.8 times. This multidimensional regulatory mechanism enables this formula to not only relieve acute symptoms but also improve long-term airway remodeling. A detection system containing 8 quality control indicators was established: potency determination: ephedrine content 1.2-1.5 mg / g (HPLC method); fingerprint chromatogram: similarity of 12 common peaks ≥0.9; biological activity: diastolic rate of isolated guinea pig tracheal strips ≥65%; safety: LD50. 50 >5000mg / kg (acute toxicity test in mice); achieving full quality traceability from raw materials to finished products.

[0022] Results of a multicenter randomized controlled trial (RCT): Overall response rate was 91.7% vs. 72.3% in the control group (P<0.01); cough symptom score decreased by 68.4%; adverse reaction rate was only 3.2% (mainly mild gastrointestinal reactions); pulmonary function tests showed an increase of 28.4% in the FEV1 / FVC ratio and a decrease of 42% in the diurnal variability of PEF.

[0023] The unit cost per treatment course is 47% lower than the ICS+LABA regimen, making it suitable for promotion in primary healthcare institutions. Spray drying technology reduces the cost per dose by 22%, and continuous production allows batch-to-batch variation to be controlled within ±3%. The developed sustained-release microgranules have three main characteristics: a dual-layer structure (0.5h immediate-release layer + 8h sustained-release layer); gastrointestinal selectivity (colon-targeted release, triggered by pH > 6.8); and patient compliance (once-daily dosing improves medication adherence by 60%).

[0024] When used in combination with ICS, it can reduce hormone dosage by 30% without affecting efficacy; when used in combination with leukotriene receptor antagonists, it exhibits an additive effect. Animal experiments have shown that this formula can downregulate the glucocorticoid-induced GRα / GRβ imbalance, providing a new strategy for integrated traditional Chinese and Western medicine treatment. Detailed Implementation

[0025] Example 1: Optimization of the preparation process and component analysis of Suhuang Zhike Decoction

[0026] This embodiment details an industrial preparation method and key quality control steps for a traditional Chinese medicine formula for relieving cough and asthma—Suhuang Zhike Tang. First, authentic medicinal materials are selected for pretreatment: Ephedra sinica is selected from newly harvested produce in Inner Mongolia, sliced, and dried to constant weight in a 60℃ constant-temperature oven; bitter almonds are made from southern almonds, with the seed coat removed and dried at low temperature, strictly controlling the moisture content to not exceed 8%. Earthworms are selected from fresh specimens, their abdomens opened and cleaned; silkworm larvae are selected from domesticated spring silkworms in their fourth molting stage and freeze-dried. After processing with an ultrafine pulverizer, the above three medicinal materials are obtained as fine powder with a particle size distribution D90 ≤ 15μm, which is confirmed to meet the requirements by laser particle size analyzer.

[0027] The remaining eleven medicinal herbs (Platycodon grandiflorus, Arctium lappa, Cicada slough, Tussilago farfara, etc.) were placed in a multi-functional extraction tank. Eight times the volume of purified water was added initially, and the mixture was heated to boiling and maintained for 2 hours. During this process, the pressure inside the tank was maintained at 0.08 MPa to preserve the constant temperature. After decoction, the solid and liquid components were separated using a horizontal centrifuge, and the supernatant was transferred to a concentration device. For the second decoction, six times the volume of water was added, and the temperature was controlled at approximately 95°C. The mixture was then decocted for another 1.5 hours before centrifugation again. The two extracts were combined and concentrated under reduced pressure at 60°C to a relative density of 1.12 (measured at 60°C). At this point, the total solids content was approximately 28%.

[0028] The aforementioned ephedra and silkworm pupae mixed fine powder and clear extract were mixed in a certain proportion and placed in a vacuum drying oven at 60°C to dry to a moisture content of ≤5%. The dried material was then crushed into coarse powder using a universal pulverizer, and an appropriate amount of honey was added as a binder. A wet granulation machine was then used to prepare a soft mass. During the granulation process, a smart moisture analyzer was used for real-time monitoring to ensure that the moisture content of the granules remained stable at 4.5%-5.0%. Finally, the granules were dried a second time in a fluidized bed dryer and then sieved through a 20-mesh sieve to obtain a finished granule product with uniform particle size and good flowability.

[0029] To verify the stability of the process, three consecutive batches of pilot production showed that the ephedrine transfer rate remained stable at 82%-85%, the glycyrrhizic acid retention rate was ≥78%, and the granules exhibited good solubility with no moisture absorption or clumping. High-performance liquid chromatography (HPLC) analysis revealed that the amygdalin content in each batch was between 0.85-0.92 mg / g, and the ammonium glycyrrhizate content was between 0.52-0.58 mg / g, meeting the preset quality control standards.

[0030] Example 2: Comparative Study on the Influence of Drug Dosage Form on Pharmacodynamics

[0031] To investigate the impact of different dosage forms on drug efficacy, this embodiment designed a comparative experiment of three dosage forms: granules, tablets, and capsules. Granules were prepared using the optimized process described in Example 1; tablets were prepared using a double-layer compression technique, with the outer layer containing immediate-release components such as ephedra and licorice, and the inner layer filled with sustained-release components such as earthworm and schisandra; capsules used enteric coating materials to ensure drug release in the intestines.

[0032] The efficacy was evaluated using a guinea pig cough model: coughing in guinea pigs was induced by ammonia nebulization, and the cough latency and the number of coughs within 2 minutes were recorded. Results showed that the granule group had a prolonged cough latency of 18.7±2.1 seconds (compared to 9.2±1.4 seconds in the control group), with an antitussive efficacy of 74.5%. The sustained-release tablet group had a slightly slower onset but a longer duration of action, reducing the number of coughs by 62% within 4 hours. The enteric-coated capsule group maintained a 58% antitussive effect 6 hours after administration. Airway hyperresponsiveness testing showed that all three dosage forms significantly reduced the increase in histamine-induced airway resistance, with the granule group showing a reduction of 67%.

[0033] Pharmacokinetic studies were conducted using LC-MS / MS to determine plasma ephedrine concentrations. In the granule group, the time to peak concentration was 0.75 hours, Cmax was 12.3 ng / mL, and AUC0-∞ was 45.6 ng·h / mL. In the sustained-release tablet group, the time to peak concentration was prolonged to 2.2 hours, Cmax was 9.8 ng / mL, but the 24-hour AUC reached 68.2 ng·h / mL, demonstrating sustained-release characteristics. Due to its enteric coating design, the capsule group released the drug in the upper small intestine, resulting in 32% higher bioavailability compared to the conventional tablets.

[0034] Regarding safety evaluation, no significant toxic reactions were observed in any dosage form group, and pathological sections showed no statistically significant differences in liver and kidney function indicators compared to the blank control group. Overall assessment suggests that granules are more suitable for rapid onset of action in the acute phase, while sustained-release tablets and enteric-coated capsules are more suitable for long-term symptom control, providing personalized options for different patient groups.

[0035] Example 3: Study on the molecular mechanism of multi-target anti-inflammatory effect

[0036] This embodiment systematically elucidates the multi-target anti-inflammatory mechanism of Suhuang Zhike Decoction through in vitro cell experiments and animal models. An LPS-induced inflammation model was established using the RAW264.7 macrophage line, and different concentrations of the drug were administered for 24 hours. ELISA results showed that the IL-6 concentration in the drug-treated groups decreased from 1200 pg / mL to 480±35 pg / mL (P<0.001), and the TNF-α concentration decreased from 850 pg / mL to 210±18 pg / mL (P<0.01). Western blot analysis indicated that the drug significantly inhibited IκBα phosphorylation, thereby blocking NF-κB nuclear translocation, with an inhibition efficiency of 63%.

[0037] In airway smooth muscle cell experiments, intracellular calcium ion concentration decreased from 182±15 nM to 81±9 nM after drug treatment (P<0.001). Patch-clamp technique confirmed that this effect was due to the drug's blocking effect on L-type calcium channels (IC50 = 3.2 μg / mL) and regulation of ryanodine receptors. Further RNA-seq analysis of differential gene expression revealed that the drug significantly upregulated β2-adrenergic receptor mRNA expression (2.8-fold) while downregulating MUC5AC mucin gene expression.

[0038] Animal experiments were conducted using an ovalbumin-sensitized asthma model, followed by sacrifice after 4 weeks of continuous drug administration. Pathological sections showed that the bronchial wall thickness in the treatment group was reduced by 47% compared to the model group, and goblet cell proliferation was reduced by 62%. ELISA analysis revealed a 54% decrease in serum IL-17A concentration, while the proportion of Foxp3+ Treg cells increased to 8.2% (compared to 3.5% in the model group). These results indicate that the drug fundamentally inhibits the development of chronic airway inflammation by regulating the Th17 / Treg balance.

[0039] Example 4: Evaluation of Clinical Efficacy and Safety

[0040] This report describes the results of a multicenter, randomized, double-blind, placebo-controlled clinical trial. 180 patients with cough-variant asthma were enrolled and randomly assigned to a treatment group (n=120) and a control group (n=60). The treatment group received Suhuang Zhike Tang granules (10g three times daily), while the control group received the same dose of placebo. The treatment course was 8 weeks, with a follow-up period of 4 weeks.

[0041] The primary efficacy endpoints were cough symptom score and changes in pulmonary function. In the treatment group, the cough score decreased from 8.2±1.5 points at baseline to 2.4±0.8 points (a decrease of 70.7%), while the decrease in the control group was only 28.6%. The morning PEF variability rate decreased from 42.3%±8.7% to 15.6%±4.2% in the treatment group, compared to 28.4%±6.5% in the control group. The absolute FEV1 value increased by 280±45 mL, and the FEV1 / FVC ratio improved by 18.2±3.5 percentage points, both significantly better than the control group (P<0.001).

[0042] Secondary efficacy endpoints included quality of life score (St. George's Respiratory Questionnaire) and frequency of emergency medication use. The total SGRQ score decreased by 19.8 points in the treatment group and by 8.4 points in the control group. The frequency of emergency medication use decreased from 4.2±1.5 times per week to 1.3±0.6 times per week, compared to 3.5±1.2 times per week in the control group.

[0043] Regarding safety, only 3 patients in the treatment group reported mild gastrointestinal reactions (2 with abdominal distension and 1 with nausea), and no abnormal liver or kidney function or serious adverse events were observed. Pharmacokinetic monitoring showed that the blood drug concentration remained stable after 8 weeks of continuous administration, and no accumulation was observed.

[0044] Example 5: Network pharmacology validation of drug action mechanism

[0045] This embodiment uses network pharmacology to predict the target and signaling pathways of Suhuang Zhike Decoction. 127 active ingredients were screened using the TCMSP database, and a protein-protein interaction network was constructed using the STRING database, revealing 23 key nodes including IL-6, TNF-α, VEGFA, and EGFR as core targets. GO enrichment analysis showed that the drug mainly participates in biological processes such as inflammatory response regulation, smooth muscle cell proliferation inhibition, and calcium ion homeostasis maintenance. KEGG pathway analysis revealed that multiple signaling pathways, including MAPK, NF-κB, and PI3K / Akt, are significantly regulated.

[0046] Molecular docking experiments verified the binding affinity of key components to their targets. Ephedrine showed an affinity of -9.2 kcal / mol for the β2-adrenergic receptor, earthworm proteinase showed a binding energy of -8.7 kcal / mol for MMP-9, and schisandrin A showed a binding energy of -7.9 kcal / mol for the NF-κB p65 subunit. These data indicate that the drugs achieve their therapeutic effects through synergistic effects involving multiple components, multiple targets, and multiple pathways.

[0047] Animal experiments further validated the network pharmacology predictions. Western blot analysis showed that after drug intervention, the expression levels of p-MAPK and p-NF-κB proteins decreased by 61% and 58%, respectively. Immunofluorescence staining revealed reduced EGFR phosphorylation levels and decreased mucus secretion in airway epithelial cells. These findings provide a scientific basis for elucidating the complex mechanisms of action of traditional Chinese medicine compound formulas.

[0048] Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. Any person skilled in the art can make various modifications and refinements without departing from the spirit and scope of the invention; therefore, the scope of protection of the present invention should be defined by the claims.

Claims

1. A traditional Chinese medicine formula for relieving cough and asthma, and its preparation method, characterized in that: It is made from the following raw materials in parts by weight: 6 parts of processed ephedra, 10 parts of bitter almond, 6 parts of raw licorice, 10 parts of platycodon, 10 parts of burdock fruit, 6 parts of cicada slough, 6 parts of silkworm, 6 parts of earthworm, 10 parts of coltsfoot flower, 10 parts of aster, 10 parts of loquat leaf, 10 parts of schisandra fruit, 10 parts of pear peel, and an appropriate amount of honey.

2. The traditional Chinese medicine for relieving cough and asthma and its preparation method according to claim 1, characterized in that: The active pharmaceutical ingredient is prepared via the following steps: a) Ephedra, earthworm, and silkworm pupae are pulverized into a fine powder; b) Boil the remaining medicinal materials twice with water, combine the decoctions and concentrate them into a clear paste; c) After mixing and drying the products from steps a) and b), honey is added and the mixture is granulated.

3. The traditional Chinese medicine for relieving cough and asthma and its preparation method according to claim 2, characterized in that: In the decoction process, the first addition of water is 8 times the weight of the medicinal materials, and the decoction is carried out for 2 hours; the second addition of water is 6 times the weight of the medicinal materials, and the decoction is carried out for 1.5 hours.

4. The traditional Chinese medicine for relieving cough and asthma and its preparation method according to claim 1, characterized in that: The drug is in the form of granules, tablets, capsules, or oral liquid preparations.

5. The traditional cough-relieving and asthma-relieving compound medicine and its preparation method according to claim 1, characterized in that... The drug exerts its therapeutic effect by antagonizing inflammatory factors IL-6 and TNF-α.

6. The traditional antitussive and antiasthmatic compound drug and its preparation method according to claim 1, characterized in that... The drug can reduce the concentration of calcium ions in bronchial smooth muscle cells.

7. The combined medication regimen for cough-variant asthma according to claim 1, which is based on a traditional antitussive and antiasthmatic compound drug and its preparation method, is characterized in that: The drug of claim 1 is used in combination with glucocorticoids or β2 receptor agonists.

8. The traditional Chinese medicine for relieving cough and asthma and its preparation method according to claim 1, characterized in that: The particle size distribution of the granules is: D90≤150μm, and water content≤5%.

9. The quality control method for a traditional antitussive and antiasthmatic compound drug and its preparation method according to claim 1, characterized in that: The amygdalin content was tested to be ≥0.8 mg / g, and the glycyrrhizic acid ammonium salt content was tested to be ≥0.5 mg / g.