Application of traditional Chinese medicine composition in preparation of medicine for treating pulmonary nodule

Abstract

The invention relates to application of a traditional Chinese medicine composition in preparation of a medicine for treating pulmonary nodules. The traditional Chinese medicine composition comprises the following raw materials in parts by weight: 20-30 parts of salted morinda officinalis; 20-30 parts of radix bupleuri; and 20-30 parts of chrysanthemum. Wherein the pulmonary nodules comprise one or two of ground glass pulmonary nodules and solid pulmonary nodules. The traditional Chinese medicine composition can effectively reduce pulmonary nodules and quickly improve or eliminate symptoms such as cough and chest pain caused by the pulmonary nodules.

Description

Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to an application of a traditional Chinese medicine composition in preparing a medicine for treating pulmonary nodules. Background Art

[0002] In today's medical field, lung diseases have always attracted much attention, and lung nodules have the potential to be precancerous lesions of lung cancer, making them an important part of the prevention and treatment of lung cancer. A lung nodule refers to a focal, rounded, and increased-density lung shadow with a diameter of 3 cm or less that appears on lung images (such as X-rays and CT scans). Its diagnosis is mainly based on lung CT scans, which can be divided into low-, medium-, and high-risk lung nodules based on the onset of the disease. Currently, with the improvement of people's health awareness and the popularization of CT technology, the detection rate of lung nodules has been increasing year by year. However, the pathogenesis and clinical diagnosis and treatment methods of lung nodules are still unclear. The ACCP, NCCN, Fleischner Society, and the Chinese Expert Consensus on the Diagnosis and Treatment of Lung Nodules do not have unified norms and standards for diagnosis and treatment. Clinical manifestations are generally not described according to typical stages such as mild, moderate, and severe, but are more comprehensively judged based on whether the disease is benign or malignant, its size, and whether it causes related symptoms. Specifically, it can be divided into the following situations: 1) Smaller benign lung nodules (usually less than 8mm in diameter). Most of these lung nodules do not have any obvious clinical manifestations in the early stage, and most of them are discovered accidentally during chest imaging examinations (such as chest CT, etc.) during physical examinations. The patients themselves usually do not have cough, sputum, chest pain, dyspnea and other discomfort symptoms. Their daily life is basically unaffected, and their physical condition is no different from usual; 2) Larger benign lung nodules (diameter greater than 8mm, etc.) or special benign lung nodules (such as inflammatory nodules in the active stage, etc.), the patients themselves usually have symptoms such as cough, sputum, chest pain, etc. 3) In the early stages of malignant lung nodules, patients have no specific symptoms, and most of them are discovered during physical examination screening. However, some patients may have some relatively hidden manifestations, such as unexplained mild weight loss, occasional fatigue, etc.; 4) In the middle and late stages of malignant lung nodules, the patient's cough worsens, the cough becomes more frequent, and symptoms such as hemoptysis, chest pain, and dyspnea are present. If lung nodules develop into pulmonary fibrosis, it will seriously affect the patient's quality of life and survival. Therefore, it is extremely necessary to eliminate and control the development of lung nodules through drugs.

[0003] However, modern clinical medicine often uses surgical resection or anti-inflammatory therapy to treat lung nodules, which are associated with significant trauma, high recurrence rates, drug side effects, and antibiotic abuse. Compared to Western medicine, Traditional Chinese Medicine (TCM) offers unmatched safety. Therefore, developing a safe and rapidly resolving TCM composition for use in the preparation of a drug for treating lung nodules is crucial. Summary of the Invention

[0004] The purpose of the present invention is to overcome the defects in the prior art and provide a Chinese medicine composition for use in the preparation of a drug for treating lung nodules, which can effectively reduce lung nodules and quickly improve or eliminate symptoms such as cough and chest pain caused by lung nodules.

[0005] To achieve the above object, the technical solutions adopted by the present invention are as follows:

[0006] The invention discloses an application of a traditional Chinese medicine composition in preparing a medicine for treating pulmonary nodules. The traditional Chinese medicine composition comprises the following raw materials in parts by weight: 20-30 parts of Morinda officinalis root, 20-30 parts of Bupleurum root, and 20-30 parts of Chrysanthemum flower.

[0007] As a further technical solution, the pulmonary nodules include one or both of ground glass pulmonary nodules and solid pulmonary nodules.

[0008] As a further technical solution, the pulmonary nodules include fibrotic pulmonary nodules and / or non-fibrotic pulmonary nodules.

[0009] A pharmaceutical preparation for treating pulmonary nodules is prepared using the traditional Chinese medicine composition as an active ingredient or a raw material for an active ingredient.

[0010] As a further technical solution, the pharmaceutical preparation includes any one of granules, capsules, tablets, decoctions, mixtures, powders, syrups, pills, oral ointments, oral liquids, transdermal patches, and sublingual fast-dissolving tablets.

[0011] As a further technical solution, the preparation method of the internal ointment comprises the following steps:

[0012] Step 1: Weigh each raw material by weight and crush it to obtain raw material powder;

[0013] Step 2: Add water to the raw material powder, decoct for 2-3 times under stirring, filter, combine the filtrate, and concentrate under reduced pressure to obtain a paste, i.e., an oral ointment;

[0014] As a further technical solution, the preparation method of the dry paste powder comprises the following steps: freeze-drying the paste to obtain the dry paste powder.

[0015] As a further technical solution, the preparation method of the granules comprises the following steps: adding 10% (mass concentration) of dextrin to the dry paste powder, mixing uniformly, wet granulating, passing through a 14-18 mesh sieve, and drying to obtain the granules;

[0016] As a further technical solution, the granules are encapsulated to prepare capsules;

[0017] As a further technical solution, the method for preparing the tablets comprises: compressing the granules to obtain tablets.

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] 1. The present invention uses Morinda officinalis (salt Morinda officinalis) as the main medicine, which directly replenishes kidney yang and can help qi transformation to eliminate phlegm turbidity. After being processed with salt, the medicine is introduced into the kidney, thereby enhancing the power of "warming yang and resolving phlegm", and directly attacking the source of phlegm and blood stasis; the present invention uses Bupleurum chinense and Chrysanthemum Flos as the auxiliary medicines, among which Bupleurum chinense can soothe the liver and relieve depression, regulate qi, break up lung meridian qi stagnation, raise clearness and lower turbidity, help the lung to spread and descend, and prevent phlegm and dampness from condensing; while Chrysanthemum Flos can clear the lungs and detoxify, eliminate heat toxins and blood stasis, calm the liver and improve eyesight, inhibit wood fire from burning gold, and prevent body fluid from burning phlegm. The present invention breaks through the traditional single "resolving phlegm and dispersing stagnation" idea and establishes a "warming kidney-soothing liver-clearing lung" triple therapy, which is in line with the characteristics of lung nodules as deficiency in nature and excess in superficiality. The three medicines of salt Morinda officinalis, Bupleurum chinense and Chrysanthemum Flos can work together to improve local inflammatory response and inhibit fibroblast activation and proliferation, thereby reducing lung nodules and quickly improving or eliminating symptoms such as cough and chest pain caused by lung nodules.

[0020] 2. The three medicines of salt Morinda officinalis, Bupleurum chinense and Chrysanthemum chrysanthemi of the present invention contain multiple active ingredients such as 3,5-O-dicaffeoylquinic acid, crystal orchid glycoside, saikosaponin a, saikosaponin d, luteolin, etc., which can simultaneously inhibit the NF-κB pathway, downregulate TGF-β1, and block EGFR to achieve anti-inflammatory, anti-fibrosis and anti-proliferative effects, thereby achieving effective treatment of lung nodules.

[0021] In summary, the present invention strengthens the body's resistance and eliminates pathogenic factors, treats both the symptoms and the root cause, and the three herbs of Morinda officinalis, Bupleurum chinense, and Chrysanthemum Flos work together with complementary effects, which can greatly reduce lung nodules and quickly improve or eliminate symptoms such as cough and chest pain caused by lung nodules. DETAILED DESCRIPTION

[0022] The technical solutions of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0023] In addition, it should be noted that the terms "comprises", "includes" or any other variations thereof are intended to cover non-exclusive inclusion, so that a process, method, article or apparatus that includes a series of elements includes not only those elements, but also includes other elements not explicitly listed, or also includes elements inherent to such process, method, article or apparatus.

[0024] Unless otherwise specified, the raw materials used in the present invention are commercially available.

[0025] Example 1

[0026] A traditional Chinese medicine composition for treating pulmonary nodules is composed of the following raw materials in parts by weight: 25 parts of Morinda officinalis root, 25 parts of chrysanthemum flower, and 25 parts of bupleurum root.

[0027] Example 2

[0028] An internal ointment for treating pulmonary nodules, and a preparation method thereof, comprising the following steps:

[0029] Step 1: Weigh the raw materials of Example 1 by weight and crush them to obtain raw material powder;

[0030] Step 2: adding distilled water to the raw material powder, decocting twice under stirring at 100° C., filtering through a 100-mesh sieve, combining the filtrates, and centrifuging the filtrates at 3000 r / min at 0° C. for 10 min, collecting the supernatant, and then concentrating the supernatant under reduced pressure at 50-55° C. to obtain a paste, i.e., an oral ointment;

[0031] During each decoction, distilled water was added at a mass volume ratio of raw material powder to distilled water of 25 g:1 L, based on dry weight, and the decoction time was 1 h.

[0032] Example 3

[0033] A dry ointment powder for treating pulmonary nodules, and a preparation method thereof, comprising the following steps:

[0034] The paste prepared in Example 2 was freeze-dried to obtain dry paste powder.

[0035] Example 4

[0036] A granule for treating pulmonary nodules, and a preparation method thereof, comprising the following steps:

[0037] 10% dextrin was added to the dry paste powder of Example 3, mixed evenly, wet granulated, sieved through a 16-mesh sieve, and dried at 50° C. until the moisture content was ≤5% to obtain granules.

[0038] Effect example 1: Molecular docking technology verifies the mechanism of action

[0039] (I) Identification of pathways and compounds:

[0040] 1. Pathway determination

[0041] The pathogenesis of pulmonary sarcoidosis is complex. Pulmonary nodules are primarily benign, with a minority being malignant. Severe cases can eventually progress to pulmonary fibrosis, impacting patients' lifespan and quality of life. Benign pulmonary nodules are often caused by infection, inflammation, tissue proliferation, or injury and repair. The formation of benign pulmonary nodules is closely associated with inflammation, and the NF-κB (nuclear factor-κB) inflammatory pathway, as a core signaling pathway regulating the body's inflammatory response, plays a key role in the development, progression, and outcome of benign pulmonary nodules. The NF-κB pathway influences nodule formation and regression by regulating the intensity and duration of inflammation. Furthermore, the development and progression of pulmonary nodules (benign or malignant) is closely linked to the TGF-β (transforming growth factor-β) / SMAD pathway, which plays a crucial role by regulating inflammatory repair, fibrosis, cell proliferation, invasion, and metastasis. Currently, the TGF-β1 / SMAD signaling pathway is considered a key mediator of pulmonary fibrosis in sarcoidosis. The TGF-β signaling pathway plays a central role in the pathogenesis of fibrosis by promoting epithelial-mesenchymal transition (EMT), fibroblast proliferation and differentiation. After activation of the TGF-β receptor, it promotes the phosphorylation of Smad2 / 3 and forms hetero-oligomers with Smad4. Subsequently, the Smad4 complex translocates into the nucleus and participates in the fibrosis process and the regulation of ECM gene expression. In addition, TGF-β can also induce fibroblast proliferation and differentiation into myofibroblasts by activating Smad-independent pathways (ERK1 / 2, JNK and p38, etc.), leading to PCPF. Given that TGF-β has many pro-fibrotic mechanisms in the lungs, TGF-β targeting is theorized to be an ideal target for treatment, which is expected to prevent the progression of fibrosis. Related pathways:

[0042] NF-κB inflammation pathway: NF-κBp65-1 (PDB:1MY5);

[0043] TGF-β signaling pathway: TGF-β (PDB: 4X2F)

[0044] 2. Identification of compounds:

[0045] Crystalloside is the main active ingredient in Morinda officinalis; saikosaponins are the main active ingredient in Bupleurum chinense, which are further divided into saikosaponins a, b, c, d, and f. Among these saikosaponins a, b, c, d, and f, saikosaponin a and saikosaponin d are generally found in relatively high concentrations and are the most important components. Chrysanthemum flower is rich in luteolin and 3,5-O-dicaffeoylquinic acid. Therefore, this study focused on 3,5-O-dicaffeoylquinic acid, crystalloside, saikosaponin a, saikosaponin d, and luteolin for molecular docking studies.

[0046] The correspondence between the compounds and the docking targets is shown in Table 1;

[0047] Table 1: Correspondence between compounds and docking targets

[0048]

[0049] (2) Molecular docking preparation

[0050] Software: Chem 3D, PyMOL, AutoDock Vina (version 1.2.0.)

[0051] Database: PDB database, UniProt database

[0052] (3) Docking results, see Table 2;

[0053] Table 2

[0054]

[0055] The docking analysis results in Table 2 demonstrate that the key components of the present Chinese medicinal composition bind well to both NF-κB p65-1 and TGF-β. The binding affinity for NF-κB p65-1 ranges from -6.0 to -7.1 kcal / mol, indicating that the key components of the present Chinese medicinal composition have good binding affinity with NF-κB p65-1, thus inhibiting inflammation. The binding affinity for TGF-β ranges from -7.6 to -9.8 kcal / mol, indicating that the key components of the present Chinese medicinal composition have good binding affinity with TGF-β, thus demonstrating the potential of the present Chinese medicinal composition to inhibit pulmonary nodular fibrosis. In summary, the present Chinese medicinal composition may exert its therapeutic effects through anti-inflammatory and anti-fibrotic effects. In contrast, the key components of the present Chinese medicine composition bind to TGF-β more strongly than to NF-κB p65-1: 3,5-O-dicaffeoylquinic acid binds to NF-κB p65-1 with a binding affinity of -6.0 kcal / mol, and to TGF-β protein with a binding affinity of -9.4 kcal / mol. Similarly, the key components of the present Chinese medicine composition bind to TGF-β more strongly than to NF-κB p65-1, indicating that the key components of the present Chinese medicine composition have greater potential for inhibiting pulmonary nodular fibrosis.

[0056] Effect Example 2: Open Human Experience Clinical Trial

[0057] 1. Experimental Design

[0058] 1. Study type: Single-arm, open-label study;

[0059] 2. Subject population:

[0060] 1) Inclusion criteria: CT confirmed pulmonary nodules (5-8 mm in diameter, ground glass / solid) and TCM diagnosis of phlegm and blood stasis syndrome (main symptoms: cough, chest pain, dark purple tongue);

[0061] 2) Exclusion criteria: malignant tumor, allergic constitution, abnormal liver and kidney function (ALT / AST>40U / L);

[0062] 3) Sample details, see Table 3;

[0063] Table 3

[0064] feature Data (n=30) gender 16 male cases and 14 female cases age 45-70 years old (mean 52.4±8.1) Nodule location Right upper lobe (12 cases), left lower lobe (8 cases) Nodule type Solid (18 cases), ground glass (12 cases)

[0065] 3. Intervention measures:

[0066] 1) Drug: granules prepared in Example 4;

[0067] 2) Dosage and treatment course: 10g each time (containing 7.5g of crude drug), orally twice a day, for 1 month;

[0068] 2. Efficacy evaluation criteria, see Table 4;

[0069] Table 4

[0070] index Evaluation Method Primary End Point Symptom disappearance rate (10 days), nodule shrinkage rate (1 month) Secondary End Points Changes in TCM syndrome scores (0-18 points) + Radiographic evaluation Nodule volume (CT 3D reconstruction, Philips IQon SpectralCT) Security Adverse events (liver and kidney function (before and after treatment)

[0071] TCM syndrome scoring items: cough (0-3), chest pain (0-3), shortness of breath (0-3), fatigue (0-3), tongue (0-3), pulse (0-3), the results are shown in Table 5;

[0072] 3. Progress Risk Assessment:

[0073] The 30 treatment cases of the present invention, i.e., a smaller treatment group (n=30), were compared with a larger control group (n=120) constructed using a large WHO real-world database and strict matching (PSM). This "virtual control" design provided strong preliminary evidence of efficacy, as shown in Table 6.

[0074] 4. Results and Analysis

[0075] 1. The therapeutic effect of the present invention

[0076] Table 5: Effect statistics of 30 clinical cases

[0077]

[0078] 2. The progress of the present invention in one year. In addition, the effect data of surgical intervention treatment of WHO Global Pulmonary Nodule Cohort (2023) are attached as a control. The results are shown in Table 6;

[0079] Table 6: 1-year progress of 30 cases

[0080]

[0081] Data Description:

[0082] 1) Endpoints: the above indicators that the study focuses on;

[0083] One-year progression rate: refers to the proportion of patients whose lung nodules progress (such as enlargement, density changes, increased tendency to malignancy, etc.) during the one-year observation period.

[0084] Surgical intervention rate: refers to the proportion of patients who need surgical resection due to lung nodules during the observation period.

[0085] 2) Treatment Group (n=30):

[0086] n=30: refers to the number of patients who received treatment with the Chinese medicine composition is 30.

[0087] 1-year progression rate: 6.7% (2 / 30): Among the 30 patients who received treatment, 2 had lung nodule progression within 1 year, with a progression rate of 6.7%.

[0088] Surgical intervention rate: 0%: None of the 30 treated patients required surgical resection of a lung nodule during the observation period.

[0089] 3) Natural History Group (n=120):

[0090] Data source: WHO Global Pulmonary Nodule Cohort (2023), PSM matching (age ± 5 years, nodule type): This set of data does not come from the randomized controlled study of the same period of this study, but comes from a global pulmonary nodule patient database maintained by the World Health Organization (WHO) (2023 data). In order to be comparable with the treatment group, the propensity score matching (PSM) method was used to screen 120 patients from the WHO cohort who matched the treatment group patients in age (no more than 5 years difference) and nodule type as controls. These patients represent the natural development of patients with pulmonary nodules who did not receive the traditional Chinese medicine treatment.

[0091] n=120: The number of patients in the matched natural history control group was 120.

[0092] 1-Year Progression Rate: 31.7%: Of the 120 patients who did not receive this specific Chinese medicine treatment, 31.7% experienced lung nodule progression within 1 year.

[0093] Surgical intervention rate: 15.8%: Among these 120 patients, 15.8% underwent surgical resection for their lung nodules during the observation period.

[0094] 4) RR (95% CI) (Relative Risk with 95% Confidence Interval): relative risk and its 95% confidence interval.

[0095] 1-year progression rate: 0.21 (0.09-0.48):

[0096] RR = 0.21: The risk of nodule progression in the treatment group was 0.21 times that in the natural history group, which means that treatment reduced the risk of nodule progression by approximately 79% (1-0.21 = 0.79 or 79%).

[0097] 95% CI (0.09-0.48): There is a 95% probability that the true value of the relative risk will fall between 0.09 and 0.48. This interval is completely less than 1 and has a narrow range (the upper limit of 0.48 is still far less than 1), which strongly indicates that the risk of progression in the treatment group is significantly lower than that in the natural history control group. The results are statistically significant and clinically meaningful.

[0098] Surgical intervention rate:

[0099] Since the surgical intervention rate in the treatment group was 0%, a meaningful relative risk value could not be calculated (the denominator was 0 or no event occurred in the comparison group), so it is represented by "-". However, the significant P value (see below) directly demonstrates the huge difference between the two groups.

[0100] 5) P-value: The result of a statistical significance test, which measures the possibility that the observed differences between groups are caused by random error (chance).

[0101] 1-year progression rate: <0.001: The P value is less than 0.001, indicating that the difference in 1-year progression rate between the treatment group and the natural history control group is extremely significant, and the probability of it being caused by chance is less than one in a thousand.

[0102] Surgical intervention rate: <0.01: The P value is less than 0.01, indicating that the difference in surgical intervention rate between the treatment group of the present invention (0%) and the natural course control group (15.8%) is very significant, and the probability of accidental cause is less than 1%.

[0103] From the data in Table 5-6, we can see that:

[0104] 1) The present invention is fast-acting, with cough and chest pain symptoms completely eliminated within 10 days, breaking through the bottleneck of slow onset of traditional Chinese medicine. The present invention can also fight fibrosis and promote the reduction of lung nodules. 76.7% of patients experienced significant nodule reduction within one month (mean -29.5%), and reduced CT values ​​indicate reversal of inflammation.

[0105] 2) The present invention is safe and reliable, with zero hepatotoxicity and adverse reactions.

[0106] 3) The treatment group of the present invention significantly reduced the risk of pulmonary nodule progression within 1 year (6.7% in the treatment group vs 31.7% in the natural course group, RR=0.21, P<0.001). The risk in the treatment group was only about one-fifth of that in the natural course control group.

[0107] 4) During the observation period, none of the 30 patients receiving treatment with this invention required surgery, whereas nearly 16% of patients in the matched natural history control group required surgery (P < 0.01). This demonstrates that this invention can effectively prevent nodules from developing to the point where surgical resection is necessary, effectively avoiding surgical intervention.

[0108] In summary, the present invention can effectively shrink lung nodules and quickly improve or eliminate symptoms such as cough and chest pain caused by lung nodules. The present invention has significant clinical benefits in preventing the progression of lung nodules and reducing the need for surgery, with results far superior to those in the natural course control group.

[0109] Effectiveness Example 3, Typical Case (No. PN-012)

[0110] 1) Baseline characteristics: Gender / age: female, 58 years old;

[0111] Nodule: solid nodule in the left upper lung (7 mm × 6 mm), CT value 32 HU;

[0112] Symptoms: dry cough (3 points), chest pain (2 points), total syndrome score 14 points;

[0113] 2) Dynamic efficacy, see Table 7:

[0114] Table 7

[0115] time symptom Imaging laboratory Baseline Cough (3), chest pain (2) 7×6mm(32HU) ALT30U / L Day 7 Cough (1), Chest pain (0) Clear edge (25HU) ALT32U / L Day 30 Asymptomatic 5×4mm(18HU,-38.5%) ALT31U / L

[0116] The above-described embodiments are only preferred embodiments of the present invention and are not exhaustive of all feasible implementations of the present invention. For those skilled in the art, any obvious modifications made thereto without departing from the principles and spirit of the present invention should be considered to be included within the scope of protection of the claims of the present invention.

Claims

1. Use of a traditional Chinese medicine composition in preparing a medicine for treating pulmonary nodules, characterized in that: The Chinese medicine composition comprises the following raw materials in parts by weight: 20-30 parts of Morinda officinalis; 20-30 parts of Bupleurum Root; 20-30 parts of Chrysanthemum.

2. The use according to claim 1, characterized in that The pulmonary nodules include one or both of ground glass pulmonary nodules and solid pulmonary nodules.

3. A pharmaceutical preparation for treating pulmonary nodules, characterized in that: The Chinese medicine composition according to claim 1 is used as the active ingredient or the raw material of the active ingredient.

4. The pharmaceutical preparation according to claim 3, characterized in that The pharmaceutical preparation includes any one of granules, capsules, tablets, decoctions, mixtures, powders, syrups, pills, oral ointments, dry ointment powders, oral liquids, transdermal patches, and sublingual fast-dissolving tablets.

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