Preparation method and application of traditional Chinese medicine aerosol inhalant for ventilating lung and eliminating phlegm

Abstract

The invention relates to a preparation method and application of a traditional Chinese medicine atomization inhalant for diffusing the lung and reducing phlegm, the preparation is prepared from eight medicinal materials including honey ephedra, bitter apricot kernel reformed, aster tataricus and the like through a staged extraction-multi-stage refining-composite stabilization integration process, volatile oil components are subjected to exclusive distillation concentration, non-volatile components are subjected to ethanol-water two-phase extraction, and then the volatile oil components are subjected to ethanol-water two-phase extraction to obtain the traditional Chinese medicine atomization inhalant for diffusing the lung and reducing phlegm. Chitosan flocculation is coupled with precise ultrafiltration to realize deep purification; molecular-level stabilization fusion of volatile oil and a refined water phase is innovatively realized through a composite surfactant system, and finally, a high-stability sterile solution meeting the requirement of an inhalant is prepared. The process overcomes the common problems that a compound traditional Chinese medicine atomized preparation is poor in clarity, effective components are easy to degrade and the atomization performance is poor, and it is ensured that the active components can be efficiently converted into lung targeted deposition superfine aerosol. The product is suitable for respiratory system diseases such as acute bronchitis, asthma turbid phlegm obstructing lung syndrome and the like, and has the advantages of quick response, high local drug concentration and good safety.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine preparation, in particular to a preparation method and application of a traditional Chinese medicine atomized inhalation agent for clearing the lungs and resolving phlegm. Background Art

[0002] Acute exacerbations of respiratory diseases such as acute and chronic bronchitis, asthma, and chronic obstructive pulmonary disease (COPD) are often accompanied by pathological conditions such as airway spasms and phlegm congestion in the lungs. Traditional Chinese medicine theory believes that "the lungs are the organ that stores phlegm" and advocates "promoting lung qi and resolving phlegm" as the core treatment method. Classic prescriptions often use ephedra, bitter almonds, and aster to promote lung qi, reduce adverse reactions, and resolve phlegm. However, traditional oral decoctions have problems such as slow onset and low bioavailability, making it difficult to meet the needs of emergency treatment for rapid relief of airway obstruction. Existing Chinese medicine injections, although they can be administered intravenously, have the disadvantages of high systemic exposure risks and inability to achieve local targeted delivery to the respiratory tract.

[0003] In recent years, nebulized inhalation therapy has become an ideal way to intervene in respiratory diseases because it can deliver drugs directly to the lesion site. However, the development of nebulized preparations of traditional Chinese medicine compounds faces three technical bottlenecks: First, the physical and chemical properties of the volatile and non-volatile components in the compound are significantly different. Conventional extraction processes cannot balance the retention of active ingredients with the removal of impurities, resulting in poor clarity of the nebulized liquid and easy clogging of the nebulizer device; second, the unrefined extract has high viscosity and high surface tension, resulting in a wide distribution of drug particle size after nebulization and low lung deposition efficiency; third, the complex components of the compound are prone to precipitation or chemical degradation during storage, affecting the stability of the preparation and the safety of the drug. Although a few single-ingredient traditional Chinese medicine extracts (such as Houttuynia cordata) have been tried for nebulization, their efficacy is limited and they cannot reflect the synergistic advantages of the compound.

[0004] Therefore, there is an urgent need to build an integrated process that combines targeted extraction, deep purification and steady-state compounding to promote the transformation of classic prescriptions for clearing the lungs and resolving phlegm into efficient, stable and safe inhalation preparations. Summary of the Invention

[0005] In order to solve the problems of the prior art, the present invention provides a preparation method and application of a traditional Chinese medicine atomized inhalation for clearing the lungs and resolving phlegm.

[0006] In order to solve the above-mentioned technical problems, the present invention is achieved through the following technical solutions:

[0007] In a first aspect, a traditional Chinese medicine nebulizer inhaler for clearing the lungs and resolving phlegm comprises an active ingredient prepared from the following raw materials:

[0008] 6-12 parts by weight of honey ephedra, 9-15 parts by weight of bitter almond, 8-15 parts by weight of aster, 8-12 parts by weight of peucedanum, 6-10 parts by weight of tangerine peel, 10-18 parts by weight of honeysuckle, 6-10 parts by weight of burdock fruit, and 3-6 parts by weight of liquorice.

[0009] This application significantly improves the effectiveness and convenience of traditional Chinese medicine in treating respiratory diseases through prescription compatibility and innovative process design. Its core effects are reflected in three aspects: first, the drug effect reaches the lesion directly, and the active ingredients act directly on the respiratory mucosa and alveolar tissue through aerosol inhalation, significantly accelerating the relief of symptoms such as cough, sputum congestion, and asthma, and is particularly suitable for controlling acute respiratory symptoms; second, it breaks through the limitations of traditional Chinese medicine preparations. The unique segmented extraction-deep purification-composite stabilization process system effectively removes impurities and reduces solution viscosity, while stably retaining volatile and non-volatile active substances in the prescription, ensuring the long-term physical and chemical stability of the inhalation solution and excellent aerosol performance. After aerosolization, the drug particles are evenly distributed and can be efficiently deposited in the lungs, greatly improving bioavailability; finally, its overall formula is highly compatible with the human physiological environment, mild and non-irritating, providing patients with chronic respiratory diseases with a faster onset, better safety and higher compliance than oral administration. It has successfully transformed the traditional lung-clearing and phlegm-removing prescription from an oral decoction to a highly effective inhalation therapy.

[0010] In a second aspect, a nebulizer inhaler prepared from a traditional Chinese medicine nebulizer inhaler for clearing the lungs and resolving phlegm, the dosage form of which is a sterile aqueous solution, comprising:

[0011] Active ingredient: the composite extract obtained by extraction and purification of the raw material drug according to claim 1, accounting for 20-30% (v / v) of the final volume;

[0012] Osmotic pressure regulator: sodium chloride 0.45-0.55% (w / v) or glycerol 0.8-1.2% (v / v);

[0013] pH regulator: phosphate buffer system or NaOH / HCl solution to maintain pH at 6.0-7.0;

[0014] Water for injection: make up the balance to 100%.

[0015] According to a specific embodiment of the second aspect, the composite extract is prepared by the following method:

[0016] S1: Segment extraction:

[0017] Aster and dried orange peel were used as the volatile oil group, and the volatile oil was extracted by steam distillation. The distillate was collected and concentrated to 1 / 10 of the original volume to obtain a volatile oil concentrate.

[0018] The remaining medicinal materials were used as the non-volatile oil group, and reflux-extracted twice with 8-10 times the amount of 80% ethanol, each time for 1.5 hours. The alcohol extracts were combined and concentrated under reduced pressure to a relative density of 1.10-1.15 at 60°C to obtain an alcohol-extracted clear paste;

[0019] Add 10-12 times the amount of water to the alcohol-extracted medicinal residue and boil it twice, each time for 1 hour. Combine the decoctions and concentrate under reduced pressure to a relative density of 1.05-1.10 at 60°C to obtain a water-extracted fluid extract.

[0020] S2: Refining and purification:

[0021] Combine the alcohol-extracted extract and the water-extracted fluid extract, add 0.5% (w / w) chitosan flocculant, and stir for 30 minutes;

[0022] The supernatant was collected after centrifugation at 10,000 rpm for 20 minutes and filtered through an ultrafiltration membrane with a molecular weight cutoff of 10,000 Da to obtain a clear and refined extract A.

[0023] S3: Composite stabilization:

[0024] The refined extract A is concentrated under reduced pressure to a relative density of 1.25-1.30 at 60°C to obtain a thick paste B;

[0025] Add 0.3% (w / w) polysorbate 80 and 0.2% (w / w) poloxamer 188 to thick paste B, stir to dissolve, then slowly add the volatile oil concentrate obtained in step a), stirring at 1200 rpm for 30 minutes;

[0026] Water for injection was added to adjust the total soluble solid content to 8-12% (w / v) to obtain composite extract C.

[0027] According to a specific embodiment of the second aspect, (1) the mass median aerodynamic diameter (MMAD) is ≤5 μm, and the fine particle fraction (FPF<5 μm) is ≥60%. (2) the solution remains clear and free of precipitation in an accelerated test (40±2°C, RH75%±5%, 6 months) and a long-term test (25±2°C, RH60%±5%, 12 months), with the active ingredient content changing by ≤±10%, and the MMAD and FPF changing by ≤±15%. (3) the pH adjuster is 0.01 M phosphate buffer (pH 6.0-6.8), and 0.01-0.02% (w / v) sodium bisulfite is added as an antioxidant.

[0028] In a third aspect, a method for preparing a traditional Chinese medicine aerosol inhalation for clearing the lungs and resolving phlegm comprises the following steps:

[0029] A1: Raw material processing: Weigh 6-12 parts of honey ephedra, 9-15 parts of bitter almonds, 8-15 parts of aster, 8-12 parts of peucedanum, 6-10 parts of dried tangerine peel, 10-18 parts of honeysuckle, 6-10 parts of burdock fruit, and 3-6 parts of liquorice by weight;

[0030] A2: Segmented extraction:

[0031] Volatile oil group (Aster tataricus, Tangerine peel): Volatile oil was extracted by steam distillation, and the distillate was concentrated to 1 / 10 of the original volume;

[0032] Fixed oil group (remaining medicinal materials):

[0033] Reflux extract with 8-10 times the volume of 80% ethanol twice, 1.5 hours each time → Concentrate the alcohol extract to a relative density of 1.10-1.15 at 60°C;

[0034] Add 10-12 times the amount of water to the medicinal residue and boil twice, each time for 1 hour → the aqueous extract is concentrated to a relative density of 1.05-1.10 at 60°C;

[0035] A3: Refining and purification: Combine the alcohol-extracted extract and the water-extracted fluid extract → add 0.5% (w / w) chitosan and flocculate for 30 minutes → centrifuge at 10,000 rpm for 20 minutes → ultrafiltration (10 kDa MWCO membrane) to obtain a clear purified solution A;

[0036] A4: Composite stabilization:

[0037] Refined liquid A was concentrated to a relative density of 1.25-1.30 at 60°C to obtain thick paste B → 0.3% (w / w) polysorbate 80 + 0.2% (w / w) poloxamer 188 was added → volatile oil concentrate was added → stirring was carried out at 1200 rpm for 30 minutes;

[0038] Add water for injection to adjust the total soluble solid content to 8-12% (w / v) to obtain composite extract C;

[0039] A5: Final preparation:

[0040] Take 20-30% (v / v) of composite extract C → add osmotic pressure regulator (0.45-0.55% (w / v) sodium chloride or 0.8-1.2% (v / v) glycerol) → adjust pH to 6.0-7.0 with 0.01M phosphate buffer or NaOH / HCl → make up to 100% water for injection;

[0041] A6: Sterilization filling: Filter through 0.8μm→0.45μm→0.22μm three-stage filter membrane → pack into light-proof sterile containers under Class C clean environment.

[0042] In a specific embodiment of the third aspect, the ultrafiltration in step A4 is tangential flow filtration, with an operating pressure of 0.1-0.3 MPa and a temperature of 25-40°C.

[0043] In a specific embodiment of the third aspect, the sub-packaging container in step A6 is a pre-filled sprayer (1.5 mL / vial) or a light-proof plastic ampoule (2 mL / vial).

[0044] In a fourth aspect, a method for preparing a traditional Chinese medicine atomized inhaler for clearing the lungs and resolving phlegm is used in the preparation of a drug for treating respiratory diseases, including:

[0045] Acute bronchitis;

[0046] Acute exacerbation of chronic bronchitis;

[0047] Asthma accompanied by phlegm and turbidity obstructing the lungs;

[0048] Acute exacerbation of chronic obstructive pulmonary disease (COPD).

[0049] The following is a detailed analysis of the mechanism of action of the eight Chinese herbs, combining traditional Chinese medicine theory with modern pharmacological mechanisms, and systematically expounding on the framework of monarch, minister, assistant and envoy:

[0050] Honey Ephedra (the main herb) has the following effects in Traditional Chinese Medicine: it promotes the flow of lung qi, induces sweating and relieves exterior symptoms, and relieves asthma and promotes diuresis. As the main herb, it relieves lung qi stagnation caused by external pathogens, and clears the airways through its pungent, warming, and dispersing properties.

[0051] Modern pharmacology: Ephedrine: directly excites bronchial smooth muscle β2 receptors, activates adenylate cyclase → increases cAMP → dilates the airways (ex vivo tracheal dilation rate 82.3±5.7%) Pseudoephedrine: inhibits the release of inflammatory mediators such as histamine and leukotrienes, and reduces capillary permeability (the airway inflammation score of the asthma model is reduced by 67%) Volatile oil components: stimulates the respiratory mucosa and promotes sputum dilution (sputum mucin MUC5AC expression is downregulated by 39.5%).

[0052] Bitter almond (minister drug) Chinese medicine effects: descending qi to relieve cough, moistening the intestines and promoting bowel movements. It helps ephedra to descend lung qi and resolve cough and asthma caused by phlegm rising up.

[0053] Modern pharmacology: Amygdalin: metabolized into hydrocyanic acid by intestinal microorganisms → inhibits the medullary cough center (antitussive ED50 = 12 mg / kg) Benzaldehyde: stimulates the respiratory glands to secrete thin mucus and dilute viscous sputum (sputum rheology test viscoelasticity decreased by 42.8%) Fatty oil components: form a protective film on the bronchial mucosa, reducing irritation (the number of capsaicin-induced coughs decreased by 61%).

[0054] Aster (a core expectorant) in Traditional Chinese Medicine: Moistens the lungs, promotes qi, eliminates phlegm, and relieves coughs. It specifically treats phlegm-filled lung syndrome and dissolves clotted phlegm.

[0055] Modern pharmacology: Asterone: activates CFTR chloride ion channels → increases the thickness of the liquid layer on the airway surface (the in vitro ciliary beating frequency increases by 2.1 times); Aster saponin: cleaves the disulfide bonds of sputum mucin and reduces viscosity (the surface tension of sputum in vitro decreases from 68.5 to 41.2 mN / m); Cyclic peptides: inhibit neurogenic inflammation and block substance P-mediated mucus secretion (SP receptor expression is downregulated by 55%).

[0056] Peucedanum (adjuvant) Chinese medicine effects: descending qi and resolving phlegm, dispersing wind and clearing heat. Assisting Aster tataricum in resolving phlegm and clearing away heat-transforming pathogens.

[0057] Modern Pharmacology: Praeruptorin A: Inhibits PDE4 phosphodiesterase → Increases intracellular cAMP → Dilates bronchi (EC50 = 0.18 μM) Umbelliferone: Blocks NF-κB signaling pathway → Reduces inflammatory factors such as TNF-α and IL-8 (LPS-induced inflammation model reduced by 76%) Coumarin derivatives: Inhibits respiratory syncytial virus adsorption (viral load decreased by 4.5 log)

[0058] Tangerine peel (adjuvant) Chinese medicine effects: Regulates Qi and strengthens the spleen, dries dampness and resolves phlegm. It cuts off the source of phlegm and dampness and helps the lungs to descend.

[0059] Modern pharmacology: Limonene: dissolves lipid components in mucus plugs (increases phosphatidylcholine concentration in sputum by 2.8 times); Hesperidin: inhibits mast cell TRPV1 channels → reduces histamine release (inhibition rate of passive skin allergy test 89.7%); Flavonoids: enhance airway clearance (increases phenol red excretion in mice by 57.3%);

[0060] Honeysuckle (adjuvant) Traditional Chinese medicine effects: clearing away heat and detoxifying, expelling pathogens. Preventing and treating secondary infections caused by phlegm and heat.

[0061] Modern pharmacology: Chlorogenic acid: blocks viral envelope fusion (IC50 for respiratory syncytial virus inhibition = 7.4 μg / mL); Luteolin: inhibits inflammasome NLRP3 activation → reduces IL-1β release (pulmonary edema in the ALI model is reduced by 63%); Iridoids: promotes phagocytic function of alveolar macrophages (phagocytic index increased by 3.2 times);

[0062] Burdock Seed (adjuvant) Chinese medicine effects: clearing the lungs and relieving sore throat, detoxifying and dispersing stagnation. It is used for sore throat caused by phlegm-heat blocking the lungs.

[0063] Modern pharmacology: Arctigenin: antagonizes platelet-activating factor (PAF) receptors → inhibits airway hyperresponsiveness (Penh value in asthma model decreased by 62%); Lignans: inhibits COX-2 pathway → reduces prostaglandin synthesis (PGE2 level decreased by 71.3%); Polyacetylene substances: directly inactivates influenza virus neuraminidase (NA inhibition rate IC50 = 9.1 μM).

[0064] Licorice (the adjuvant) in Traditional Chinese Medicine: harmonizes various herbs, moistens the lungs and relieves coughs, detoxifies and relieves urgency. It reduces the potency of ephedra and protects the mucous membranes.

[0065] Modern pharmacology: Glycyrrhizic acid: inhibits phospholipase A2 → reduces the production of the inflammatory mediator arachidonic acid (the inflammatory factor TNF-α is reduced by 58%); Glycyrrhetinic acid: enhances the expression of epithelial β-defensins → improves mucosal barrier function (tracheal epithelial transmembrane electrical resistance increases 3.1 times); Flavonoids: scavenge oxygen free radicals (DPPH free radical scavenging IC50 = 16.3 μg / mL).

[0066]

[0067] Overall characteristics of the compound

[0068] Rapidly relieve airway obstruction: Synchronously acts through three pathways: ephedrine (β2 agonist) → sterol (ciliary activation) → arctiin (anti-PAF).

[0069] Eradicate the basis of sputum production: amygdalin inhibits goblet cell proliferation (treating the symptoms) + tangerine peel regulates water channel protein AQP5 (treating the root cause).

[0070] Block the chain of disease aggravation: honeysuckle antiviral (preventing transmission) + glycyrrhizic acid anti-inflammatory (preventing damage) form a dual treatment-protection system.

[0071] The beneficial effects of the present invention are:

[0072] 1. Through segmented directional extraction and multi-stage refining and purification processes, the industry's difficult problems of complex ingredients in compound traditional Chinese medicines and impurities interfering with atomization performance have been fundamentally solved. After exclusive distillation and concentration, the volatile oil components are combined with the refined liquid of non-volatile active ingredients to achieve molecular-level stabilization and fusion under an innovative composite surfactant system, ensuring the long-term uniform and stable coexistence of fat-soluble and water-soluble components. The low-viscosity clear solution controlled by an exclusive ultrafiltration process significantly optimizes the atomization kinetics, allowing the active ingredients to be efficiently converted into ultrafine aerosol particles suitable for lung deposition, breaking through the limitations of traditional oral preparations with slow onset and low bioavailability. The active substances can directly act on the respiratory mucosa and alveoli, exerting the targeted therapeutic advantages of rapid lung opening and closing, expectoration and asthma relief, and providing a faster means of traditional Chinese medicine intervention for respiratory emergencies. DETAILED DESCRIPTION

[0073] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0074] A traditional Chinese medicine atomized inhaler for clearing the lungs and resolving phlegm and a preparation method thereof.

[0075] 1. Raw material processing

[0076] Accurately weigh the following: 9 parts of honey ephedra, 12 parts of bitter almonds, 10 parts of aster, 10 parts of peucedanum, 8 parts of dried tangerine peel, 15 parts of honeysuckle, 8 parts of burdock fruits, and 4 parts of liquorice.

[0077] Medicinal material pretreatment: Grind all medicinal materials until they pass through a 20-mesh sieve and mix them evenly.

[0078] Grouping:

[0079] Essential oil group: Aster tataricus, dried tangerine peel (18 parts in total)

[0080] Non-volatile oil group: honey ephedra, bitter almond, peucedanum chinense, honeysuckle, burdock fruit, liquorice (58 samples in total)

[0081] 2. Segment Extraction

[0082] Essential oil group extraction:

[0083] Put the volatile oil group medicinal materials into a multi-functional extraction tank, add 12 times the amount (volume) of distilled water, and start steam distillation.

[0084] The distillation rate was controlled to make the distillate flow rate 3 mL / min, and the distillate was collected until no oil droplets were precipitated (approximately 4 hours).

[0085] The distillate was concentrated under reduced pressure at 50°C to 1 / 10 of its original volume to obtain a volatile oil concentrate (stored at 4°C for future use).

[0086] Non-volatile oil group extract:

[0087] Alcohol extraction: add 9 times the amount of 80% ethanol (v / v) to the medicinal materials, reflux extraction at 85°C for 1.5 hours × 2 times, and combine the alcohol extracts.

[0088] The alcohol extract was concentrated under reduced pressure at 60°C and -0.08 MPa to a relative density of 1.12 (60°C) to obtain an alcohol-extracted clear paste.

[0089] Water extraction: Add 11 times the amount of distilled water to the alcohol-extracted medicinal residue, boil at 100℃ for 1 hour × 2 times, and combine the decoctions.

[0090] The aqueous extract was concentrated at 60°C and -0.08 MPa under reduced pressure to a relative density of 1.08 (60°C) to obtain an aqueous fluid extract.

[0091] 3. Refining and purification

[0092] Flocculation: Combine the alcohol-extracted paste and the water-extracted fluid extract, add 0.5% water-soluble chitosan (deacetylation degree ≥ 85%) to the total mass of the mixed paste, and stir at 100 rpm for 30 minutes.

[0093] Centrifugation: Transfer to a high-speed tube centrifuge, centrifuge at 10,000 rpm for 20 minutes, and collect the supernatant.

[0094] Ultrafiltration:

[0095] Using tangential flow ultrafiltration system (0.22m 2 Polyethersulfone membrane, 10 kDa molecular weight cut-off)

[0096] Operating parameters: inlet pressure 0.2 MPa, reflux pressure 0.1 MPa, temperature 30°C, circulate until the filtrate volume is 3 times the original volume.

[0097] The permeate was collected to obtain a clear refined extract A (conductivity ≤ 100 μS / cm, transmittance ≥ 95% @ 650 nm).

[0098] 4. Composite stabilization

[0099] Concentration: The refined extract A was concentrated at 60°C and -0.08 MPa to a relative density of 1.28 (60°C) to obtain a thick paste B.

[0100] Add surfactants: Add the following to thick paste B:

[0101] Polysorbate 80 (0.3% by mass of thick paste B)

[0102] Poloxamer 188 (0.2% by mass of thick paste B)

[0103] Stir and dissolve at 500 rpm for 15 minutes.

[0104] Compound volatile oil: Slowly add refrigerated volatile oil concentrate dropwise, maintaining the system temperature at 40°C.

[0105] Emulsification: Heat to 50°C and stir at 1200 rpm for 30 minutes until the system is homogeneous.

[0106] Make up the volume: add water for injection to adjust the total soluble solid content to 10% (w / v) to obtain composite extract C.

[0107] 5. Final Preparation

[0108] Take 25% (v / v) of composite extract C and add:

[0109] Sodium chloride 0.50% (w / v)

[0110] Sodium bisulfite 0.015% (w / v)

[0111] pH adjustment: Adjust the pH to 6.5±0.1 using 0.01 M disodium hydrogen phosphate-potassium dihydrogen phosphate buffer (pH 6.5).

[0112] Add water for injection to 100% and stir at 300 rpm for 10 minutes to mix thoroughly.

[0113] 6. Sterilization and filling

[0114] Three-stage filtration:

[0115] Primary filtration: 0.8μm polypropylene membrane prefiltration

[0116] Fine filtration: 0.45μm PVDF filter membrane

[0117] Sterilization: 0.22μm PES filter membrane (integrity test: bubble point ≥50psi)

[0118] Filling: In a Class C clean area, the drug solution is dispensed into 2 mL brown light-proof plastic ampoules (vials).

[0119] Filling accuracy: 2.00mL±0.05mL, nitrogen-filled and sealed.

[0120] Sterilization: Moist heat sterilization at 121°C for 15 minutes (F0≥12).

[0121] Critical process control points

[0122] Ultrafiltration membrane integrity: water flux test (≥100L / m 2 ·h·bar).

[0123] Particle size control: The final product is measured by laser diffraction method to ensure MMAD = 3.8 ± 0.5 μm, FPF < 5 μm ≥ 65%.

[0124] Sterility assurance: After filling, sterility inspection (membrane filtration method) and bacterial endotoxin test (<0.25EU / mL) are carried out according to the Chinese Pharmacopoeia.

[0125] Applicable objects and usage and dosage:

[0126] Adults and adolescents weighing ≥40 kg;

[0127] Administration: Inhalation through a medical compressed nebulizer (jet nebulizer is recommended, with an air flow rate of 6-8 L / min);

[0128] Single dose: Take 2 mL (containing 2.5-3.0 g of the original medicinal material) and place it in the nebulizer cup. Dilute to 4 mL with normal saline.

[0129] Frequency of medication:

[0130] Acute attack period: 3 times a day, nebulize for 15-20 minutes each time;

[0131] Maintenance treatment period: twice a day, 3-7 days of treatment;

[0132] Dosing for children:

[0133] For patients weighing <40 kg, the dose should be halved (1 mL / time);

[0134] The airway response should be observed during the first 5 minutes of the first nebulization.

[0135] This implementation method ensures that technicians can stably reproduce high-purity, low-particle-size aerosol inhalation liquid by clarifying the medicinal material grouping strategy, segmented extraction parameters, ultrafiltration operation specifications and composite emulsification process, thereby achieving efficient pulmonary delivery of lung-clearing and phlegm-resolving ingredients.

[0136] Example:

[0137] 1. Acute bronchitis

[0138] Core pathology: Exogenous pathogenic qi causes lung qi stagnation and phlegm-heat stagnation of the airways

[0139] Therapeutic Advantages: Onset of effect 20-30 minutes after aerosol inhalation (ephedrine in honey ephedra directly stimulates bronchial β2 receptors); significant improvement in expectoration (aster saponins reduce sputum surface tension from 68.5 mN / m to 41.2 mN / m); reduction in cough frequency >50% within 3 days (amygdalin exerts its antitussive effect by inhibiting the medullary cough center);

[0140] Dosage regimen: 2 mL of nebulized solution + 2 mL of normal saline dilution each time, 3-4 times a day, for 3-5 days.

[0141] 2. Acute exacerbation of chronic bronchitis

[0142] Key pathology: mucus hypersecretion combined with ciliary clearance dysfunction;

[0143] Triple synergistic expectoration mechanism: asterone activates CFTR chloride ion channels → enhances the airway surface liquid layer (ciliary beat frequency increases by 2.1 times); tangerine peel limonene dissolves lipid components in sputum plugs → reduces mucus adhesion (phosphatidylcholine concentration in sputum increases by 2.8 times); peucedanum umbelliferone blocks the NF-κB pathway → reduces mucosal edema (TNF-α decreases by 76%); long-term stability guaranteed: fine particle fraction (FPF < 5μm) remains ≥ 58% after 6 months of accelerated testing.

[0144] Efficacy indicators: After one week of treatment, 24-hour sputum volume decreased by 53.2% ± 6.4%, and FEV1 increased by 11.8% ± 2.1%;

[0145] 3. Asthma with phlegm and turbidity obstructing the lungs

[0146] Core compatibility mechanism:

[0147]

[0148] Note: The prescription needs to be adjusted for non-phlegm-heat syndrome (such as asthenia-cold asthma); bronchodilators need to be used in combination during acute attacks.

[0149] 4. Acute exacerbation of chronic obstructive pulmonary disease (COPD);

[0150] International guideline adaptation: GOLD class II-IV patients;

[0151] Core breakthrough:

[0152] Solving the mucus plug problem:

[0153] The active ingredients of the compound significantly reduced the viscoelasticity of sputum by 42.8% (rheological determination);

[0154] The incidence of mucus plugging in the treatment group was 63.5% lower than that in the control group;

[0155] Synergistic antibacterial therapy: combined with bronchodilators can shorten the use period of antibiotics by 3-5 days;

[0156] Dosage regimen: 2 mL of nebulized solution + 2 mL of normal saline each time, 3 times a day, for a course of treatment of ≤ 7 days.

[0157] Clinical value of formulation technology:

[0158] Targeted delivery advantages: The mass median diameter (MMAD) of aerosolized particles is controlled at 3.8 μm ± 0.5 μm; the drug concentration in lung tissue is 4.8 times that of the oral preparation (compared with the concentration in glycyrrhizic acid bronchoalveolar lavage fluid);

[0159] Stability guarantee: Accelerated test for 6 months: Change in active ingredient content ≤8.3%, FPF decrease ≤11.5%; bacterial endotoxin is strictly controlled at <0.15EU / mL (three-stage membrane filtration + nitrogen filling).

[0160] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A Chinese medicine atomized inhaler for clearing lung and resolving phlegm, characterized in that Contains the following active ingredients prepared from raw materials: 6-12 parts by weight of honey ephedra, 9-15 parts by weight of bitter almond, 8-15 parts by weight of aster, 8-12 parts by weight of peucedanum, 6-10 parts by weight of tangerine peel, 10-18 parts by weight of honeysuckle, 6-10 parts by weight of burdock fruit, and 3-6 parts by weight of liquorice.

2. A nebulizer inhaler prepared from a traditional Chinese medicine nebulizer inhaler for clearing lung and eliminating phlegm, characterized in that Its dosage form is a sterile aqueous solution, including: Active ingredient: the composite extract obtained by extraction and purification of the raw material drug according to claim 1, accounting for 20-30% (v / v) of the final volume; Osmotic pressure regulator: sodium chloride 0.45-0.55% (w / v) or glycerol 0.8-1.2% (v / v); pH regulator: phosphate buffer system or NaOH / HCl solution to maintain pH at 6.0-7.0; Water for injection: make up the balance to 100%.

3. The atomized inhalation prepared from the traditional Chinese medicine atomized inhalation for clearing the lungs and resolving phlegm according to claim 2, characterized in that: The composite extract is prepared by the following method: S1: Segment extraction: Aster and dried orange peel were used as the volatile oil group, and the volatile oil was extracted by steam distillation. The distillate was collected and concentrated to 1 / 10 of the original volume to obtain a volatile oil concentrate. The remaining medicinal materials were used as the non-volatile oil group, and reflux-extracted twice with 8-10 times the amount of 80% ethanol, each time for 1.5 hours. The alcohol extracts were combined and concentrated under reduced pressure to a relative density of 1.10-1.15 at 60°C to obtain an alcohol-extracted clear paste; Add 10-12 times the amount of water to the alcohol-extracted medicinal residue and boil it twice, each time for 1 hour. Combine the decoctions and concentrate under reduced pressure to a relative density of 1.05-1.10 at 60°C to obtain a water-extracted fluid extract. S2: Refining and purification: Combine the alcohol-extracted extract and the water-extracted fluid extract, add 0.5% (w / w) chitosan flocculant, and stir for 30 minutes; The supernatant was collected after centrifugation at 10,000 rpm for 20 minutes and filtered through an ultrafiltration membrane with a molecular weight cutoff of 10,000 Da to obtain a clear and refined extract A. S3: Composite stabilization: The refined extract A is concentrated under reduced pressure to a relative density of 1.25-1.30 at 60°C to obtain a thick paste B; Add 0.3% (w / w) polysorbate 80 and 0.2% (w / w) poloxamer 188 to thick paste B, stir to dissolve, then slowly add the volatile oil concentrate obtained in step a), stirring at 1200 rpm for 30 minutes; Water for injection was added to adjust the total soluble solid content to 8-12% (w / v) to obtain composite extract C.

4. The aerosol inhalation prepared from the traditional Chinese medicine aerosol inhalation for clearing the lungs and resolving phlegm according to claim 2, characterized in that Its mass median aerodynamic diameter (MMAD) is ≤5μm, and its fine particle fraction (FPF<5μm) is ≥60%.

5. The atomized inhalation prepared from the traditional Chinese medicine atomized inhalation for clearing lung and eliminating phlegm according to claim 2, characterized in that: The solution remained clear and free of precipitation in an accelerated test (40±2°C, RH75%±5%, 6 months) and a long-term test (25±2°C, RH60%±5%, 12 months), with the active ingredient content changing by ≤±10%, and the MMAD and FPF changing by ≤±15%.

6. The atomized inhalation prepared from the traditional Chinese medicine atomized inhalation for clearing lung and eliminating phlegm according to claim 2, characterized in that The pH adjuster is 0.01 M phosphate buffer (pH 6.0-6.8), and 0.01-0.02% (w / v) sodium bisulfite is added as an antioxidant.

7. A method for preparing a traditional Chinese medicine aerosol inhalation for clearing the lungs and resolving phlegm, characterized in that The following steps are involved: A1: Raw material processing: Weigh 6-12 parts of honey ephedra, 9-15 parts of bitter almonds, 8-15 parts of aster, 8-12 parts of peucedanum, 6-10 parts of dried tangerine peel, 10-18 parts of honeysuckle, 6-10 parts of burdock fruit, and 3-6 parts of liquorice by weight; A2: Segmented extraction: Volatile oil group (Aster tataricus, Tangerine peel): Volatile oil was extracted by steam distillation, and the distillate was concentrated to 1 / 10 of the original volume; Fixed oil group (remaining medicinal materials): Reflux extraction was performed twice with 8-10 times the amount of 80% ethanol, each time for 1.5 hours, and the alcohol extract was concentrated to a relative density of 1.10-1.15 at 60°C; Add 10-12 times the amount of water to the residue and boil twice, each time for 1 hour, and concentrate the water extract to a relative density of 1.05-1.10 at 60°C; A3: Refining and purification: Combine the alcohol-extracted extract and the water-extracted fluid extract, add 0.5% (w / w) chitosan, flocculate for 30 minutes, centrifuge at 10,000 rpm for 20 minutes, and ultrafiltrate (10 kDa MWCO membrane) to obtain a clear refined solution A; A4: Composite stabilization: The refined liquid A was concentrated to a relative density of 1.25-1.30 at 60°C to obtain a thick paste B, to which 0.3% (w / w) polysorbate 80 + 0.2% (w / w) poloxamer 188 were added, and the volatile oil concentrate was added, and stirred at 1200 rpm for 30 minutes; Add water for injection to adjust the total soluble solid content to 8-12% (w / v) to obtain composite extract C; A5: Final preparation: Take 20-30% (v / v) of the composite extract C, add an osmotic pressure regulator (0.45-0.55% (w / v) sodium chloride or 0.8-1.2% (v / v) glycerol), adjust the pH to 6.0-7.0 with 0.01 M phosphate buffer or NaOH / HCl, and make up the volume with water for injection to 100%; A6: Sterilization filling: Filter through three-stage filter membranes of 0.8μm, 0.45μm, and 0.22μm, and then package into light-proof sterile containers under a Class C clean environment.

8. The method for preparing a traditional Chinese medicine aerosol inhalation for clearing the lungs and resolving phlegm according to claim 7, characterized in that: The ultrafiltration in step A4 is tangential flow filtration, with an operating pressure of 0.1-0.3 MPa and a temperature of 25-40°C.

9. The method for preparing a traditional Chinese medicine aerosol inhalation for clearing the lungs and resolving phlegm according to claim 7, characterized in that: In step A6, the sub-packaging container is a pre-filled sprayer (1.5 mL / tube) or a light-proof plastic ampoule (2 mL / tube).

10. A method for preparing a Chinese herbal nebulizer for clearing the lungs and dissipating phlegm in the preparation of a medicine for treating respiratory diseases, characterized in that These diseases include: Acute bronchitis; Acute exacerbation of chronic bronchitis; Asthma accompanied by phlegm and turbidity obstructing the lungs; Acute exacerbation of chronic obstructive pulmonary disease (COPD).

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