Traditional Chinese medicine composition and traditional Chinese medicine preparation for treating sub-solid pulmonary nodules and application of traditional Chinese medicine composition and traditional Chinese medicine preparation

Abstract

The invention provides a traditional Chinese medicine composition for treating sub-solid pulmonary nodule, a traditional Chinese medicine preparation and application thereof. The traditional Chinese medicine composition is prepared from the following components in parts by weight: 5 to 10 parts of cortex phellodendri, 10 to 15 parts of rhizoma atractylodis, 15 to 20 parts of radix achyranthis bidentatae, 20 to 30 parts of raw semen coicis, 10 to 15 parts of radix platycodonis, 10 to 15 parts of raw liquorice root and 10 to 15 parts of radix ranunculi ternati. The traditional Chinese medicine composition is subjected to traditional Chinese medicine formula screening according to the theory of traditional Chinese medicine and the theory of syndrome differentiation and treatment, the formula is rigorous, and aiming at sub-solid pulmonary nodule patients differentiated as phlegm-dampness stagnated heat in traditional Chinese medicine, multiple indexes such as the average diameter and the volume of the nodule can be obviously reduced, the progress of the sub-solid pulmonary nodule is inhibited, and the clinical symptoms of the patients are improved; the anxiety and depression mood of a patient is relieved, and no obvious drug-related adverse reaction exists.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, specifically including a traditional Chinese medicine composition, traditional Chinese medicine preparation and its application for treating subsolid pulmonary nodules. Background Technology

[0002] There are currently no clearly effective drugs for treating subsolid pulmonary nodules (SSN) during long-term follow-up observation. Traditional Chinese medicine (TCM) intervention has become one of the treatment options for patients. However, due to the high heterogeneity of SSN, there is currently a lack of efficacy standards for TCM treatment of SSN. Most clinical studies rely on imaging observations of nodule diameter and density changes as efficacy evaluation indicators, which has certain limitations. Further screening of the advantageous population for TCM treatment and accurate evaluation of the effectiveness rate of TCM treatment for pulmonary nodules are of great clinical value.

[0003] The applicant has developed a traditional Chinese medicine composition for the prevention and treatment of subsolid pulmonary nodules, along with its preparation method and application. This composition includes Platycodon grandiflorus, Inula japonica, Glycyrrhiza uralensis, Scutellaria baicalensis, Prunus armeniaca, Salvia miltiorrhiza, Ligusticum chuanxiong, Vespa nidus, Buthus martensii, and Gallus gallus domesticus (gizzard lining). It can be used to treat patients with subsolid pulmonary nodules diagnosed by traditional Chinese medicine as having a phlegm-blood stasis syndrome. It has the effects of regulating qi, removing blood stasis, resolving phlegm, detoxifying, and dispersing nodules. It can effectively inhibit the progression of pulmonary nodules, reduce the trend of increasing nodule numbers, and significantly improve patients' clinical symptoms such as cough and chest tightness, with no significant drug-related adverse reactions. However, according to the principles of treatment, there are currently few reports on other types of subsolid pulmonary nodules diagnosed by traditional Chinese medicine, such as those with phlegm-dampness and heat stagnation. Further development of new clinical treatment plans is still needed. Summary of the Invention

[0004] To address the aforementioned problems in the existing technology, the first objective of this invention is to provide a traditional Chinese medicine composition for treating subsolid pulmonary nodules. This composition can effectively treat subsolid pulmonary nodules caused by phlegm-dampness stagnation and heat syndrome, significantly reduce multiple indicators such as the average diameter and volume of the nodules, inhibit the progression of subsolid pulmonary nodules, improve patients' clinical symptoms, and alleviate patients' anxiety and depression.

[0005] The second objective of this invention is to provide a traditional Chinese medicine preparation for treating subsolid pulmonary nodules.

[0006] A fourth objective of this invention is to provide the use of the traditional Chinese medicine composition or preparation described above in the preparation of a medicament for treating subsolid pulmonary nodules.

[0007] To achieve the first objective mentioned above, the technical solution adopted by the present invention includes:

[0008] This invention discloses a traditional Chinese medicine composition for treating subsolid pulmonary nodules. By weight, the traditional Chinese medicine composition includes 5-10 parts of Phellodendron bark, 10-15 parts of Atractylodes lancea, 15-20 parts of Achyranthes bidentata, 20-30 parts of raw Coix seed, 10-15 parts of Platycodon grandiflorus, 10-15 parts of raw Glycyrrhiza uralensis, and 10-15 parts of Uncaria rhynchophylla, and is denoted as the Simiao Sanjie Formula.

[0009] Guided by the theory of "regulating Qi and detoxifying," this invention posits that SSN (Small-Screen Nodule Syndrome) originates from the disordered ascending and descending of Qi in the body, leading to dysfunction of the Triple Burner's Qi transformation function and disordered body fluid metabolism. This gradually evolves into pathological products such as "phlegm and dampness," which stagnate in the tortuous lung collaterals through the Triple Burner pathway, resulting in the radiographic manifestation of ground-glass opacities in the lungs. These tangible pathological products simultaneously affect the free flow of Qi in the upper burner (heart and lungs), further exacerbating Qi stagnation and creating a vicious cycle. Furthermore, prolonged Qi stagnation generates internal heat, which combines with pathological products such as phlegm and dampness, leading to a prolonged and difficult-to-cure condition. This gradually accumulates into cancerous toxins, promoting nodule progression. Therefore, treatment should focus on regulating Qi, resolving phlegm, and eliminating dampness to clear the source, while clearing heat, relieving stagnation, and detoxifying to halt the progression of the disease.

[0010] Targeting the pathogenesis of SSN, this invention utilizes the Simiao Sanjie Formula to treat SSN patients with phlegm-dampness stagnation and heat syndrome. In this formula, Phellodendron bark is bitter, cold, and drying, with a descending nature, excelling at clearing damp-heat in the lower burner. Atractylodes rhizome is pungent, bitter, and drying, with a penetrating nature, capable of dispelling accumulated damp-heat. These two herbs work together as the principal herbs; Coix seed is mildly diuretic and promotes diuresis, providing an outlet for dampness; Uncaria rhynchophylla is pungent and warm, specifically entering the lung meridian to resolve phlegm-dampness accumulation. These two herbs, together, assist the principal herb in dispelling dampness, serving as the assistant herbs; Platycodon grandiflorus opens and disperses lung qi, carrying the medicine into the lungs, while Achyranthes bidentata has a downward-moving nature, guiding the pathogenic factors downwards. These two herbs, used together, mutually regulate qi, promoting smooth qi flow, serving as the adjuvant herbs; Glycyrrhiza uralensis clears heat and harmonizes the other herbs, serving as the guiding herb. The combined effects of these herbs are to promote qi circulation, resolve phlegm, promote diuresis, clear heat, detoxify, and dissipate nodules.

[0011] The medicinal materials used in the formula of this invention have the following functions and indications:

[0012] Phellodendron bark: The dried bark of *Phellodendron chinense* Schneid. or *Phellodendron amurense* Rupr., both belonging to the Rutaceae family. It is bitter and cold in nature, and enters the kidney and bladder meridians. It has the effects of clearing heat and drying dampness, purging fire and eliminating steaming heat, detoxifying and healing sores. It is used for damp-heat diarrhea, jaundice, leukorrhea, urinary tract infections, beriberi, flaccidity, bone steaming fever, night sweats, seminal emission, sores and carbuncles, and eczema and itching. Salt-processed Phellodendron bark nourishes yin and reduces fire, and is used for yin deficiency with excessive fire, night sweats, and bone steaming fever.

[0013] Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz., both belonging to the Asteraceae family, is a pungent, bitter, and warm-natured rhizome that enters the spleen, stomach, and liver meridians. It has the effects of drying dampness and tonifying the spleen, dispelling wind and cold, and improving eyesight. It is used for dampness obstructing the middle jiao, abdominal distension, diarrhea, edema, beriberi, rheumatic pain, common cold due to wind-cold, night blindness, and blurred vision.

[0014] Achyranthes bidentata Bl., the dried root of the plant Achyranthes bidentata Bl., is bitter, sweet, sour, and neutral in nature. It enters the liver and kidney meridians and has the effects of removing blood stasis and promoting menstruation, tonifying the liver and kidneys, strengthening tendons and bones, promoting urination and relieving strangury, and guiding blood downward. It is used for amenorrhea, dysmenorrhea, soreness of the waist and knees, weakness of tendons and bones, strangury, edema, headache, dizziness, toothache, canker sores, hematemesis, and epistaxis.

[0015] Raw Job's tears: The dried, mature seed kernel of *Coix lacryma-jobi* L. var. *ma-yuen* (Roman.) Stapf, a plant of the Poaceae family. It is sweet, bland, and cool in nature, and enters the spleen, stomach, and lung meridians. It has the effects of promoting diuresis and eliminating dampness, strengthening the spleen and stopping diarrhea, relieving numbness, draining pus, and detoxifying and dispersing nodules. It is used for edema, beriberi, dysuria, spleen deficiency diarrhea, dampness-induced numbness and contracture, lung abscess, intestinal abscess, warts, and tumors.

[0016] Platycodon grandiflorum (Jacq.) A.DC., a plant in the Campanulaceae family. It is bitter, pungent, and neutral in nature, and enters the Lung meridian. It has the effects of clearing the lungs, relieving sore throat, resolving phlegm, and draining pus. It is used for cough with excessive phlegm, chest tightness, sore throat and hoarseness, and lung abscess with purulent sputum.

[0017] Raw licorice: The dried root and rhizome of *Glycyrrhiza uralensis* Fisch., *Glycyrrhiza inflata* Bat., or *Glycyrrhiza glabra* L. (all belonging to the Fabaceae family). It is sweet and neutral in nature, and enters the heart, lung, spleen, and stomach meridians. It has the effects of tonifying the spleen and replenishing qi, clearing heat and detoxifying, resolving phlegm and relieving cough, relieving spasms and pain, and harmonizing other herbs. It is used for spleen and stomach weakness, fatigue, palpitations, shortness of breath, cough with excessive phlegm, abdominal and limb spasms and pain, carbuncles and boils, and to alleviate the toxicity and harshness of other drugs.

[0018] Cat's Claw Herb: The dried tuberous root of Ranunculus ternatus Thunb., a plant in the Ranunculaceae family. It is sweet, pungent, and warm in nature, and enters the liver and lung meridians. It has the effects of dispersing blood stasis, reducing swelling, and detoxifying.

[0019] Furthermore, by weight, the traditional Chinese medicine composition includes 10 parts of Phellodendron bark, 15 parts of Atractylodes lancea, 15 parts of Achyranthes bidentata, 30 parts of raw Coix seed, 15 parts of Platycodon grandiflorus, 10 parts of raw Glycyrrhiza uralensis, and 10 parts of Uncaria rhynchophylla.

[0020] To achieve the second objective mentioned above, the technical solution adopted by the present invention includes:

[0021] This invention discloses a traditional Chinese medicine preparation for treating subsolid pulmonary nodules, wherein the active ingredients of the traditional Chinese medicine preparation include the traditional Chinese medicine composition described above.

[0022] Furthermore, the dosage form of the traditional Chinese medicine preparation is tablets, decoction, granules, capsules, oral liquid or ointment, preferably granules.

[0023] Furthermore, the traditional Chinese medicine preparation also includes pharmaceutically acceptable excipients.

[0024] Furthermore, the granules are prepared according to the following steps:

[0025] Weigh out each Chinese herbal ingredient according to the prescription, add water to decoct, filter, concentrate the filtrate, and make granules.

[0026] Furthermore, the daily dosage of the granules is 6g each time, twice a day.

[0027] To achieve the third objective mentioned above, the technical solution adopted by the present invention includes:

[0028] This invention discloses the application of the traditional Chinese medicine composition or preparation described above in the preparation of a drug for treating subsolid pulmonary nodules.

[0029] Furthermore, the drug is used to treat subsolid pulmonary nodules with phlegm-dampness stagnation and heat syndrome.

[0030] Beneficial effects of this invention:

[0031] This invention discloses a traditional Chinese medicine composition for treating subsolid pulmonary nodules with phlegm-dampness stagnation and heat syndrome. This composition is based on traditional Chinese medicine theory and the principle of syndrome differentiation and treatment, with a rigorous formulation. Specifically targeting patients with subsolid pulmonary nodules diagnosed with phlegm-dampness stagnation and heat syndrome according to traditional Chinese medicine, it can significantly reduce multiple indicators such as the average diameter and volume of nodules, inhibit the progression of subsolid pulmonary nodules, improve patients' clinical symptoms, and alleviate patients' anxiety and depression, without significant drug-related adverse reactions. Attached Figure Description

[0032] Figure 1 The diagram shows the enrollment process for a clinical trial.

[0033] Figure 2 This shows a comparison of the difference between the mean diameter of nodules and the baseline in the control group and the traditional Chinese medicine group during the clinical trial.

[0034] Figure 3 This shows a comparison of the difference in the average CT values ​​of nodules before and after the trial in the control group and the traditional Chinese medicine group in the clinical trial.

[0035] Figure 4 This shows a comparison of the difference in nodule volume before and after the trial in the control group and the traditional Chinese medicine group in the clinical trial.

[0036] Figure 5 This shows a comparison of the differences in TCM symptom scores before and after the trial in the control group and the TCM group in the clinical trial.

[0037] Figure 6 This shows a comparison of the differences in mood scale (PHQ-9, GAD-7, ISI) scores before and after the trial between the control group and the traditional Chinese medicine group in the clinical trial.

[0038] Figure 7 This shows the evaluation of tumor-suppressing efficacy in different experimental groups during the tumor suppression experiment. Figure 7 In the diagram, A represents the changes in tumor growth, and B represents the changes in mouse body weight. Detailed Implementation

[0039] To more clearly illustrate the present invention, the following description, in conjunction with preferred embodiments and accompanying drawings, further clarifies the invention. It should be understood that the described embodiments are merely some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0040] Example

[0041] The formulation of the traditional Chinese medicine composition is as follows:

[0042] 10g of Phellodendron bark, 15g of Atractylodes lancea rhizome, 15g of Achyranthes bidentata root, 30g of raw Coix seed, 15g of Platycodon grandiflorus root, 10g of raw Glycyrrhiza uralensis root, and 10g of Uncaria rhynchophylla herb.

[0043] According to the above formula, take Phellodendron bark, Atractylodes lancea, Achyranthes bidentata, raw Coix seed, Platycodon grandiflorus, raw Glycyrrhiza uralensis, and Uncaria rhynchophylla, add water and decoct, filter, concentrate the filtrate into an extract, dry and granulate to obtain the product, named Simiao Sanjie Formula.

[0044] Clinical trials

[0045] 1. Clinical Data

[0046] 1.1 Research Subjects

[0047] The study cases in this clinical trial were high-risk SSN patients who visited Guang'anmen Hospital of China Academy of Chinese Medical Sciences between May and September 2024, and whose TCM syndrome was phlegm-dampness stagnation and heat syndrome.

[0048] 1.2 Diagnostic criteria

[0049] 1.2.1 Western Medicine Diagnostic Criteria

[0050] Western medicine diagnostic criteria: Referring to the "Chinese Expert Consensus on the Diagnosis and Treatment of Pulmonary Nodules (2024 Edition)", "Guidelines for Lung Cancer Screening and Early Diagnosis and Treatment in China (2021 Edition)", "Fleischner Society Guidelines for Small Pulmonary Nodules (2017 Edition)", and the Lung-RADS pulmonary nodule grading system, high-risk SSNs are defined as those meeting one of the following criteria:

[0051] ①Lung-RADS diagnosis of category 4B or above;

[0052] ②Those diagnosed with high-risk pulmonary nodules by the AI-assisted system and after review of images by two imaging experts.

[0053] 1.2.2 Diagnostic Criteria for Traditional Chinese Medicine Syndromes

[0054] Traditional Chinese Medicine (TCM) diagnostic criteria: The criteria for "phlegm-dampness and heat stagnation syndrome" were established by referring to the "Guiding Principles for Clinical Research of New Chinese Herbal Drugs," "Traditional Chinese Medicine Diagnostics" published by China Traditional Chinese Medicine Press, and "Internal Medicine of Traditional Chinese Medicine" published by China Traditional Chinese Medicine Press, and in conjunction with comprehensive clinical practice.

[0055] Main symptoms: cough with yellow phlegm, bitter and sticky mouth, abdominal distension and poor appetite, heaviness and fatigue in the limbs;

[0056] Secondary symptoms: obesity, dry mouth and thirst, irritability and heat intolerance, heaviness and dizziness in the head, dark yellow urine, burning or painful and difficult urination, foul-smelling or sticky and unsatisfactory bowel movements;

[0057] Tongue and pulse: The tongue is red, swollen, with teeth marks on the sides, and has a thick, greasy yellow coating; the pulse is soft and rapid or slippery and rapid.

[0058] If two primary symptoms and at least one secondary symptom are present, or at least one primary symptom and at least two secondary symptoms are present, and this is combined with tongue and pulse diagnosis, a diagnosis of phlegm-dampness-heat syndrome can be made.

[0059] 1.3 Inclusion Criteria

[0060] (1) Age 18-75 years old;

[0061] (2) The average diameter of the largest nodule is 6-15 mm and it has been stable for ≥3 months;

[0062] (3) The TCM syndrome differentiation is consistent with the diagnosis of phlegm-dampness-heat syndrome.

[0063] (4) Meets the criteria for determining a high-risk SSN;

[0064] (5) Voluntarily participate in this study and sign the informed consent form.

[0065] 1.4 Exclusion Criteria

[0066] (1) The total number of pulmonary nodules is ≥10;

[0067] (2) Patients with concurrent lung cancer and other tumor diseases;

[0068] (3) Children, pregnant women, patients with mental illness or who are breastfeeding;

[0069] (4) Patients with liver and kidney dysfunction;

[0070] (5) Patients who are allergic to the Chinese medicine they are taking;

[0071] (6) Those who are currently participating in other clinical studies.

[0072] 1.5 Standards for shedding and rejection

[0073] (1) Patients who experience serious adverse events and have to discontinue the trial;

[0074] (2) Patients who refuse to undergo follow-up;

[0075] (3) Patients who cannot be contacted for various reasons;

[0076] (4) Patients whose incomplete data affects the final evaluation;

[0077] (5) The participant requested to withdraw from the study.

[0078] 2. Research Content and Methods

[0079] This study protocol has passed the ethical review of the Medical Ethics Committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences (approval number 2024-082-KY) and has been registered for clinical trials (approval number ChiCTR2400084457). This is a practical randomized controlled trial based on real-world principles. The study subjects were high-risk SSN patients with phlegm-dampness stagnation and heat syndrome. Based on a randomized controlled trial or a shared decision-making model, patients were divided into a control group and a traditional Chinese medicine (TCM) group according to their wishes. Each group consisted of 45 patients, for a total of 90 subjects. The TCM group received oral administration of Simiao Sanjie Fang for 24 weeks, while the control group was followed up regularly according to guidelines. The primary outcome measure was the efficacy rate of TCM treatment for SSN. Secondary outcome measures included SSN progression rate, stabilization rate, TCM syndrome efficacy evaluation, and psychological status evaluation (PHQ-9 depression score, GAD-7 anxiety score, and ISI insomnia score). Safety indicators included complete blood count, blood biochemistry, and other adverse reactions to comprehensively evaluate the efficacy and safety of Simiao Sanjie Fang in treating high-risk SSN (phlegm-dampness stagnation and heat syndrome). The following will combine... Figure 1 Please provide an explanation.

[0080] 2.1 Treatment Plan

[0081] (1) Control group: Follow-up was conducted regularly according to the imaging follow-up cycle recommended in the "Guidelines for Screening and Early Diagnosis and Treatment of Lung Cancer in China (2021, Beijing)", without drug intervention.

[0082] (2) Traditional Chinese Medicine Group: Patients were followed up regularly and treated with Simiao Sanjie Formula for 24 weeks. The patients included in the study started taking Simiao Sanjie Formula of Example 1 orally from the first day of the first cycle. The decoction pieces were provided by the outpatient pharmacy of Guang'anmen Hospital of China Academy of Chinese Medical Sciences. Each person was prepared into 12g of decoction granules, 6g each time, orally, twice a day, half an hour after breakfast and dinner.

[0083] 2.2 Observation Indicators

[0084] Demographic data collection: name, gender, age, past medical history, smoking history, drinking history, family history of cancer, etc.

[0085] 2.2.1 Main therapeutic indicators

[0086] Based on the "Expert Consensus on the Diagnosis and Management of Pulmonary Nodules in Traditional Chinese Medicine Based on Screening of High-Risk Groups for Lung Cancer" and relevant experts' clinical experience, we formulated evaluation criteria for the efficacy of TCM treatment of pulmonary nodules.

[0087] Nodule treatment efficacy rate = (number of cases where the target nodule was partially absorbed + number of cases where the target nodule was completely absorbed) / total number of cases in the group × 100%.

[0088] Note: Partial absorption of the target nodule:

[0089] Follow-up LDCT showed the target nodule, with no signs of nodule progression, and met one of the following conditions:

[0090] (1) ① The average diameter of the target nodule is 5-10 mm, and the average diameter is reduced by ≥30% compared with the previous one;

[0091] ②The average diameter of the target nodule is >10mm, and the average diameter has decreased by ≥20% compared to the previous value;

[0092] (2) The average CT value (HU) of the target nodule decreased by ≥15% or by 50 HU;

[0093] (3) The solid component of the target nodule was reduced;

[0094] (4) The target nodule volume is reduced by ≥25%.

[0095] Note: Complete absorption of the target nodule:

[0096] The target nodule was not visible on follow-up LDCT.

[0097] 2.2.2 Secondary efficacy indicators

[0098] Nodule progression rate = (Number of cases where the target nodule has progressed / Total number of cases in this group) × 100%.

[0099] Note: Target nodule progress:

[0100] The target nodule is considered to have progressed if one of the following conditions is met:

[0101] (1) ① The average diameter of the target nodule is 5-10 mm, and the average diameter has increased by ≥30% compared with the previous one;

[0102] ②The average diameter of the target nodule is greater than 10 mm, and the average diameter has increased by ≥20% compared to the previous value;

[0103] (2) The CT value (HU) of the target nodule increases by ≥15% or by 50 HU;

[0104] (3) The average diameter of the solid component of the target nodule increased by >1.5 mm;

[0105] (4) The volume of the target nodule increases by ≥25%;

[0106] (5) The target nodule shows malignant signs such as lobulation, spiculation, pleural indentation, and vascular convergence.

[0107] Nodule stabilization rate = (Number of stable cases with target nodules / Total number of cases in this group) × 100%.

[0108] Note: The target nodule is stable.

[0109] Follow-up LDCT showed no progression or absorption of the target nodule.

[0110] Measurement method: CT scan should be performed during deep inspiration to measure lung nodules. AI-assisted imaging experts mark the largest SSN on the lung window image and measure and calculate the volume, average density, and average diameter of the cross section at the largest level (the average of the longest diameter and the vertical diameter, rounded to the nearest integer, in mm).

[0111] Traditional Chinese Medicine (TCM) syndrome evaluation: A TCM syndrome scoring scale for phlegm-dampness-heat syndrome was developed based on the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine Drugs" to evaluate changes in the subjects' TCM syndromes. Symptoms were categorized into five levels based on severity: extremely severe (4 points), severe (3 points), moderate (2 points), mild (1 point), and none (0 points). Changes in TCM syndrome scores before and after the trial were observed and recorded.

[0112] Psychological status assessment: The psychological status of the subjects was assessed using the Depression Screening Scale (PHQ-9), the Anxiety Screening Scale (GAD-7), and the Insomnia Intensity Scale (ISI).

[0113] 2.2.3 Safety Indicators

[0114] Patients in the traditional Chinese medicine group underwent routine blood tests and blood biochemistry (liver and kidney function) every 3 months during the treatment period, and adverse reactions during the treatment were recorded.

[0115] 2.2.4 Follow-up time and method

[0116] During the treatment period, the traditional Chinese medicine group underwent safety visits every 12 weeks ± 1 week, including complete blood count and blood biochemistry (liver and kidney function) tests, and the use of the study drug was recorded. Both groups underwent TCM syndrome evaluation, psychological status evaluation, and CT imaging evaluation after week 24. The follow-up deadline was March 1, 2025.

[0117] 2.3 Statistical Methods

[0118] Statistical analysis will be performed using SPSS 26.0 software, employing a two-tailed test. A p-value < 0.05 will be considered statistically significant. Normally distributed continuous data will be expressed as mean ± standard deviation. For comparisons between groups, if the data are homogeneous in variance, a two-sample t-test is used. If the variances are unequal, a corrected t-test is used. For comparisons within groups, a paired t-test is used. Non-normally distributed continuous data are described using the median (interquartile range) [M(P25,P75)], and the Wilcoxon rank-sum test for grouped continuous data is used. Categorical data are expressed as frequency or percentage, and comparisons between groups are performed using the Pearson chi-square test or Fisher's exact test.

[0119] 3 Results

[0120] 3.1 Baseline Data

[0121] This study recruited 90 patients with SSN, with 45 patients in the traditional Chinese medicine (TCM) group and 45 patients in the control group. Follow-up at weeks 12 and 24: 6 patients dropped out in the TCM group (2 underwent surgery during treatment, 2 were lost to follow-up, and 2 did not take the medication after being prescribed), and 4 patients dropped out in the control group (2 underwent surgery during follow-up, and 2 were lost to follow-up). Ultimately, 39 patients in the TCM group and 41 patients in the control group, totaling 80 patients, completed treatment and follow-up, as shown in Table 1.

[0122] Table 1. Patients' Research Completion Status

[0123] Project Group Traditional Chinese medicine group N (%) Control group N (%) Total N (%) Enrollment status 45(100.00) 45(100.00) 90(100.00) Has the research plan been completed? - - - yes 39(86.67) 41(91.11) 80(88.89) no 6(13.33) 4(8.89) 10(11.11)

[0124] There was no statistically significant difference in the general information of the two groups of patients (Table 2) (P>0.05).

[0125] Table 2. Demographic data and clinical characteristics of the two groups of patients

[0126]

[0127]

[0128] 3.2 Results Analysis

[0129] 3.2.1 Key Outcome Indicators

[0130] The primary outcome measure was the effectiveness rate of traditional Chinese medicine treatment, which included relevant indicators such as the mean diameter of nodules, mean CT value, and volume. Due to differences in baseline information between the two groups, the difference test was primarily used to compare the differences in outcome indicators before and after treatment between the two groups, thereby reducing the impact of baseline differences on the outcome variable.

[0131] (1) Changes in the average diameter of the largest SSN before and after treatment

[0132] Regarding the average diameter of the SSN, the normality test showed that the data were skewed. The Wilcoxon two-sample rank-sum test was used to analyze the two groups, and the results are shown in Tables 3-1 and 3-2. Figure 2 .

[0133] Comparison between the traditional Chinese medicine group and the control group: There was no statistically significant difference in the baseline distribution of the mean diameter of SSNs between the two groups (P>0.05), indicating comparability. After 24 weeks of treatment, the mean diameter of SSNs in the traditional Chinese medicine group decreased compared with that in the control group, but the difference was not statistically significant (P>0.05).

[0134] Within-group comparison between the traditional Chinese medicine group and the control group: After 24 weeks of treatment, the average diameter of SSN in the traditional Chinese medicine group was significantly reduced (P<0.05), while the average diameter of SSN in the control group was increased, but the difference was not statistically significant (P>0.05).

[0135] Intergroup comparison of the difference from baseline after 24 weeks: The intergroup comparison of the difference in the mean diameter of SSN before and after the test between the Chinese medicine group and the control group was statistically significant (P<0.05), indicating that after 24 weeks of treatment, Simiao Sanjie Formula can effectively reduce the mean diameter of nodules.

[0136] Table 3-1 Comparison of average nodule diameter before and after the test between the traditional Chinese medicine group and the control group (mm)

[0137]

[0138] Note: Compared with before treatment, * P<0.05.

[0139] Table 3-2 Comparison of the difference (mm) between the average diameter of nodules after treatment and the baseline between the traditional Chinese medicine group and the control group.

[0140]

[0141] Note: Compared with the control group, ** P<0.01.

[0142] (2) Comparison of mean SSN CT values ​​before and after treatment in the two groups

[0143] Regarding the average CT value of SSN, the normality test showed that the data were skewed. The Wilcoxon two-sample rank-sum test was used to analyze the two groups. The results are shown in Tables 4-1 and 4-2. Figure 3 .

[0144] Comparison between the traditional Chinese medicine group and the control group: There was no statistically significant difference in the baseline distribution of mean SSN CT values ​​between the two groups (P>0.05), indicating comparability. After 24 weeks of treatment, there was no statistically significant difference between the traditional Chinese medicine group and the control group (P>0.05).

[0145] Within-group comparison between the traditional Chinese medicine group and the control group: After 24 weeks of treatment, the mean CT value of SSN in the traditional Chinese medicine group increased compared with the previous value, but the difference was not statistically significant (P>0.05), while the mean CT value of SSN in the control group increased significantly compared with the previous value, and the difference was statistically significant (P<0.05).

[0146] Intergroup comparison of the difference from baseline after 24 weeks: There was no statistically significant difference in the mean CT value of SSN between the Chinese medicine group and the control group before and after the test (P>0.05), indicating that after 24 weeks of treatment, Simiao Sanjie formula was not able to effectively improve the mean CT value of nodules.

[0147] Table 4-1 Comparison of mean CT values ​​of nodules before and after the test between the traditional Chinese medicine group and the control group (HU)

[0148]

[0149] Note: Compared with before treatment, * P<0.05.

[0150] Table 4-2 Comparison of the mean CT value difference from baseline after nodule treatment between the traditional Chinese medicine group and the control group (HU)

[0151]

[0152] (3) Comparison of SSN volume before and after treatment in the two groups:

[0153] Regarding the SSN volume, the normality test showed that the data were skewed. The Wilcoxon two-sample rank-sum test was used to analyze the two groups. The results are shown in Tables 5-1 and 5-2. Figure 4 .

[0154] Comparison between the traditional Chinese medicine group and the control group: There was no statistically significant difference in the baseline distribution of SSN volume values ​​between the two groups (P>0.05), indicating comparability. After 24 weeks of treatment, there was no statistically significant difference between the traditional Chinese medicine group and the control group (P>0.05).

[0155] Within-group comparison between the traditional Chinese medicine group and the control group: After 24 weeks of treatment, the SSN volume in the traditional Chinese medicine group decreased compared with the previous period, but the difference was not statistically significant (P>0.05), while the SSN volume in the control group increased significantly compared with the previous period, and the difference was statistically significant (P<0.05).

[0156] Comparison of the difference from baseline between the two groups after 24 weeks: The difference in SSN volume before and after the test between the Chinese medicine group and the control group was statistically significant (P<0.05), indicating that after 24 weeks of treatment, Simiao Sanjie Formula can effectively reduce the volume of nodules.

[0157] Table 5-1 Comparison of nodule volume before and after the test between the traditional Chinese medicine group and the control group (mm) 3 )

[0158]

[0159] Note: Compared with before treatment, * P<0.05.

[0160] Table 5-2 Comparison of nodule volume differences from baseline after treatment between the traditional Chinese medicine group and the control group (mm) 3 )

[0161]

[0162] Note: Compared with the control group, * P<0.05.

[0163] (4) Comparison of SSN changes before and after treatment in the two groups

[0164] According to the efficacy evaluation criteria, the changes in SSN before and after treatment in the two groups were evaluated based on indicators such as average diameter, average CT value, and volume. The results showed that the effective rate of traditional Chinese medicine treatment for SSN was 20.5%, which was significantly higher than that of the control group (P<0.05). The analysis results are shown in Table 6.

[0165] Table 6. Changes in SSN before and after treatment in the two groups (cases)

[0166]

[0167]

[0168] Note: Compared with the control group, * P<0.05.

[0169] (6) Comparison of efficacy before and after treatment in the two groups

[0170] The efficacy was evaluated based on the changes in SSN before and after treatment in the two groups. The results showed that the effective rate in the traditional Chinese medicine group was 20.5%, the stabilization rate was 53.8%, and the progression rate was 25.6%, while the effective rate in the control group was 2.4%, the stabilization rate was 61.0%, and the progression rate was 36.6%. There was a statistically significant difference in the treatment effect of nodules between the two groups (P<0.05).

[0171] The Bonferroni multiple comparison method was used to compare the differences in nodule effectiveness, stability, and progression between the two groups. The results showed that there was only a statistical difference in effectiveness between the two groups (P<0.05), while there was no statistical difference in nodule stability rate and nodule progression rate (see Table 7).

[0172] Table 7 Comparison of treatment efficacy between the traditional Chinese medicine group and the control group (cases)

[0173] Group efficient Stablize progress <![CDATA[X 2 ]]> P control group 1(2.4％) 25(61.0％) 15(36.6％) 6.746 <![CDATA[0.034 * ]]> Traditional Chinese Medicine Group 8(20.5％) 21(53.8％) 10(25.6％) - -

[0174] Note: Compared with the control group, * P<0.05.

[0175] 3.2.2 Secondary Outcome Indicators

[0176] (1) Comparison of TCM syndrome scores before and after treatment in the two groups

[0177] Regarding the TCM symptom scores, the normality test showed that the data in this group were skewed. The Wilcoxon two-sample rank-sum test was used to analyze the two groups. The results are shown in Tables 8-1 and 8-2. Figure 5 .

[0178] Comparison between the traditional Chinese medicine (TCM) group and the control group: There was no statistically significant difference in the baseline distribution of TCM symptom scores between the two groups (P>0.05), indicating comparability. After 24 weeks of treatment, the scores in the TCM group decreased significantly compared with those in the control group, and the difference was statistically significant (P<0.001).

[0179] Within-group comparison between the Chinese medicine group and the control group: After 24 weeks of treatment, the TCM symptom scores of patients in the Chinese medicine group decreased significantly (P < 0.001), while the TCM symptom scores of patients in the control group did not change significantly (P > 0.05).

[0180] Comparison of the differences from baseline between the two groups after 24 weeks: The difference between the Chinese medicine group and the control group before and after the trial was statistically significant (P<0.01), indicating that after 24 weeks of treatment, Simiao Sanjie Formula can effectively improve the related symptoms of patients with SSN phlegm-dampness stagnation and heat syndrome.

[0181] Table 8-1 Comparison of TCM symptom scores before and after treatment between the TCM group and the control group

[0182]

[0183]

[0184] Table 8-2 Comparison of TCM symptom scores from baseline between the TCM group and the control group after treatment.

[0185]

[0186] (2) Evaluation of psychological status before and after treatment in the two groups

[0187] Regarding the scores on the PHQ-9, GAD-7, and ISI self-assessment scales, normality tests showed that all three groups exhibited a skewed distribution. Wilcoxon's two-sample rank-sum test was used to analyze the two groups. The results are shown in Table 9-1 and Table 9-2. Figure 6 .

[0188] Comparison of PHQ-9, GAD-7, and ISI self-rating scale scores between the traditional Chinese medicine group and the control group: There were no statistically significant differences in the baseline distribution of the three self-rating scale scores between the two groups (P>0.05), indicating comparability. After 24 weeks of treatment, the scores of all three self-rating scales in the traditional Chinese medicine group were significantly lower than those in the control group, with statistically significant differences (P<0.05).

[0189] Comparison of PHQ-9, GAD-7, and ISI self-rating scale scores between the traditional Chinese medicine group and the control group: After 24 weeks of treatment, the scores of the three self-rating scales in the traditional Chinese medicine group decreased significantly (P < 0.001), while the scores of the traditional Chinese medicine symptoms in the control group did not change significantly (P > 0.05).

[0190] The differences in PHQ-9, GAD-7, and ISI self-rating scale scores between the two groups after 24 weeks were compared with the baseline. The differences between the Chinese medicine group and the control group before and after the trial were statistically significant (P < 0.001), indicating that after 24 weeks of treatment, Simiao Sanjie Formula can effectively improve anxiety and depression symptoms, improve sleep quality, and promote the improvement of psychological state in patients with SSN.

[0191] Table 9-1 Comparison of PHQ-9, GAD-7, and ISI self-assessment scale scores before and after treatment in the two groups

[0192]

[0193] Note: Compared with before treatment, * P<0.05; *** P < 0.001; compared with the control group, △ P<0.05.

[0194] Table 9-2 Comparison of PHQ-9, GAD-7, and ISI scores from baseline in the two groups of SSN patients after 24 weeks.

[0195]

[0196]

[0197] Note: Compared with the control group, the comparison between groups is as follows. *** P<0.001.

[0198] 3.3 Adverse reactions occurring during the trial in the traditional Chinese medicine group

[0199] During the treatment, no significant abnormalities were observed in the blood routine and blood biochemical indicators (liver function and kidney function) of the patients in the traditional Chinese medicine group before and after treatment. Among them, 3 patients experienced diarrhea after taking the medicine, which was tolerated and resolved spontaneously. It was determined to be a mild adverse event, with an adverse reaction rate of 7.7%. The remaining patients did not experience any adverse reactions.

[0200] 4 Discussion

[0201] Current clinical studies often use changes in diameter and density as indicators of efficacy evaluation, which has certain limitations. This study uses artificial intelligence-assisted imaging experts to statistically analyze nodule-related information in two groups of patients before and after the trial. It incorporates multiple indicators such as average nodule diameter, average CT value, and volume to formulate a comprehensive efficacy evaluation standard, which can more comprehensively reflect the efficacy of traditional Chinese medicine treatment. Because this study included patients with persistent SSN (those who did not disappear after 3 months of follow-up), related studies have shown that such nodules have potential malignancy, but are often indolent, progressing slowly over a long period, exhibiting growth characteristics of early-stage lung adenocarcinoma. This study, through analysis of nodule diameter changes in the two groups, found that after 24 weeks of treatment, the Simiao Sanjie formula significantly reduced the average diameter of SSNs, proving that the Simiao Sanjie formula can inhibit nodule progression and reduce the risk of cancer, while the control group showed no statistically significant difference before and after the trial. Furthermore, studies have shown that the mean CT value (representing density) of SSN is positively correlated with the risk of nodule malignancy, and can quantitatively reflect the degree of malignancy of SSN. Its general evolution pattern is that from precancerous lesions to invasive adenocarcinoma, the mean CT value of nodules increases continuously. However, in this study, there was no statistically significant difference between the two groups before and after treatment and between the treatment and baseline. However, the results analysis showed that the nodule density in the traditional Chinese medicine group was stable, while the control group showed a progressive trend.

[0202] Volume is also an important indicator for assessing nodule risk. Studies show that a 25% increase in nodule volume from baseline is defined as progression. Furthermore, the doubling time of nodule volume has been extensively studied. Malignant nodules exhibit different doubling times depending on their pathological stage; the doubling time for pre-invasive lesions and invasive lesions is 400-600 days and less than 400 days, respectively. In this study, we found that the nodule volume in the control group increased after 24 weeks, while the nodule volume in the traditional Chinese medicine group decreased. The difference between the two groups after treatment and baseline was statistically significant, suggesting that the Simiao Sanjie formula can reduce nodule volume and inhibit nodule cancer progression. In addition, spiculation, lobulation, bronchial signs, and pleural traction on SSN imaging all suggest malignancy.

[0203] This study analyzed the clinical efficacy evaluation established using multiple indicators. The results showed that the effective rate of traditional Chinese medicine (TCM) treatment for subsolid pulmonary nodules (SSN) was 20.5%, significantly higher than that of the control group, and no significant adverse reactions were observed, preliminarily demonstrating the effectiveness and safety of TCM treatment for subsolid pulmonary nodules. However, the treatment efficacy rate in this study was lower than that in previous studies, which may be related to the inclusion of the subjects (those with persistently stable nodules) and the efficacy evaluation criteria (comprehensive evaluation of multiple imaging indicators).

[0204] Regarding TCM clinical symptoms, this study included SSN patients with phlegm-dampness-heat syndrome. These patients often presented with symptoms such as yellow phlegm, bitter and sticky mouth, epigastric fullness and poor appetite, and heaviness in the limbs. After 24 weeks of treatment, the TCM symptom score in the TCM group was significantly better than that in the control group, demonstrating that TCM treatment can significantly improve the related symptoms of phlegm-dampness-heat syndrome in SSN patients. Furthermore, SSN patients often experience significant psychological burden during the long follow-up period due to concerns about cancer risk, frequently exhibiting anxiety and depression, accompanied by decreased sleep quality. Studies have shown that negative emotions can further induce the activation and proliferation of tumor cells, thereby promoting tumor transformation and forming a vicious cycle. This study used the PHQ-9, GAD-7, and ISI self-rating scales to observe changes in anxiety, depression, and sleep quality in both groups before and after the trial. The results showed that both groups had significant anxiety and depression before the trial, accompanied by decreased sleep quality. After 24 weeks, the TCM group showed significantly better efficacy than the control group, indicating that TCM can effectively improve patients' anxiety, depression, and other negative emotions, and improve sleep quality.

[0205] In conclusion, traditional Chinese medicine treatment for SSN has significant advantages over the "follow-up observation" approach alone. The Simiao Sanjie formula can effectively inhibit the progression of SSN in patients with phlegm-dampness stagnation and heat syndrome, improve patients' clinical symptoms, and reduce their anxiety and depression, without any obvious drug-related adverse reactions. It is worthy of further in-depth clinical research and widespread application.

[0206] To better demonstrate the efficacy of the traditional Chinese medicine composition provided by this invention in inhibiting nodule shrinkage, the following tumor inhibition experiment was further conducted.

[0207] Tumor suppression experiment

[0208] 1. Experimental Materials

[0209] 1.1 Laboratory Animals

[0210] This study used 4-6 week old male C57BL / 6 mice (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.), weighing 18-22g, which were acclimatized in an SPF-grade housing for 1 week.

[0211] 1.2 Experimental Cells

[0212] The Lewis lung cancer cell line from mice was purchased from the National Experimental Cell Resource Sharing Platform.

[0213] 1.3 Experimental Drugs

[0214] The formula for the Simiao Sanjie Decoction in Example 1 was prepared using Chinese herbal medicines provided by the pharmacy of Guang'anmen Hospital, China Academy of Chinese Medical Sciences. Cisplatin was purchased from Qilu Pharmaceutical Co., Ltd.

[0215] 1.4 Experimental Apparatus

[0216] Table 10 lists the experimental instruments required for the tumor suppression experiment.

[0217] Table 10 Experimental Instruments Required for Tumor Suppression Experiment

[0218]

[0219]

[0220] 2 Experimental methods

[0221] 2.1 Model Establishment and Grouping of Experimental Animals

[0222] In the laboratory, Lewis cells from mouse lung cancer are routinely cultured. After reaching a certain quantity, the cells are collected and counted to produce a concentration of 5*10⁻⁶ cells / mL. 6 Cell suspension of 0.2 mL / mL was administered to 24 SPF-grade male C57BL / 6 mice, each with 0.2 mL of cell suspension subcutaneously injected into the right axilla.

[0223] After successful modeling, the animals were randomly divided into 4 groups of 6 each: a control group (daily gavage with equal volume of distilled water), a chemotherapy group (cisplatin administration, 2 mg / kg, intraperitoneal injection, once every three days), a traditional Chinese medicine group (human equivalent dosage conversion based on body surface area reduction method), a low-dose traditional Chinese medicine group (SSD-L, 7.48 g / kg, gavage, once daily), and a high-dose traditional Chinese medicine group (SSD-H, 29.9 g / kg, gavage, once daily), which were administered by gavage for 10 consecutive days.

[0224] 2.2 Determination and calculation of tumor volume, body weight, and tumor inhibition rate in each group of mice

[0225] Tumor volume and body weight were measured in mice every two days. Tumor volume was calculated as follows: Tumor volume (mm²) 3 = Length (mm) × Width (mm) × Width (mm) × π / 6.

[0226] The tumor inhibition rate is calculated using the following formula: Inhibition rate (%) = (Tumor weight in the control group - Tumor weight in the treatment group) / Tumor weight in the control group × 100%.

[0227] 2.3 Statistical Methods

[0228] Data analysis was performed using GraphPadPrism 8.0 software. One-way ANOVA was used for comparisons between groups, and LSD method was used for pairwise comparisons between groups. *P < 0.05 was considered statistically significant.

[0229] 3 Results

[0230] To verify the efficacy of the Simiao Sanjie formula, an experiment was conducted to evaluate its antitumor effects. Figure 7 The results showed that tumor growth was significantly inhibited after 10 days of treatment with the high-dose traditional Chinese medicine (TCM). The body weight of mice treated with the TCM was not significantly affected, indicating that the treatment with Simiao Sanjie Decoction had no obvious toxicity. Figure 7 (Chinese medicine B). Ten days later, the tumor weight was measured, and the tumor inhibition rate in the high-dose Chinese medicine group was 27.29%.

[0231] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all the implementation methods here. All obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. A traditional Chinese medicine composition for treating subsolid pulmonary nodules, characterized in that, The traditional Chinese medicine composition comprises, by weight, 5-10 parts of Phellodendron bark, 10-15 parts of Atractylodes lancea, 15-20 parts of Achyranthes bidentata, 20-30 parts of raw Coix seed, 10-15 parts of Platycodon grandiflorus, 10-15 parts of raw Glycyrrhiza uralensis, and 10-15 parts of Uncaria rhynchophylla.

2. The traditional Chinese medicine composition according to claim 1, characterized in that, The traditional Chinese medicine composition comprises, by weight, 10 parts of Phellodendron bark, 15 parts of Atractylodes lancea rhizome, 15 parts of Achyranthes bidentata root, 30 parts of raw Coix seed, 15 parts of Platycodon grandiflorus root, 10 parts of raw Glycyrrhiza uralensis root, and 10 parts of Uncaria rhynchophylla herb.

3. A traditional Chinese medicine preparation for treating subsolid pulmonary nodules, characterized in that, The active ingredients of the traditional Chinese medicine preparation include the traditional Chinese medicine composition as described in claim 1 or 2.

4. The traditional Chinese medicine preparation according to claim 3, characterized in that, The dosage forms of the traditional Chinese medicine preparations are tablets, decoctions, granules, capsules, oral liquids, or ointments.

5. The traditional Chinese medicine preparation according to claim 3, characterized in that, The traditional Chinese medicine preparation also includes pharmaceutically acceptable excipients.

6. The traditional Chinese medicine preparation according to claim 3, characterized in that, The dosage form of the traditional Chinese medicine preparation is granules.

7. The traditional Chinese medicine preparation according to claim 6, characterized in that, The granules were prepared according to the following steps: Weigh each Chinese herbal ingredient according to the prescription, add water and decoct, filter, concentrate the filtrate into an extract, dry and granulate to obtain granules.

8. The traditional Chinese medicine preparation according to claim 6, characterized in that, The daily dosage of the granules is 6g each time, twice a day.

9. The use of the traditional Chinese medicine composition as described in claim 1 or 2, or the traditional Chinese medicine preparation as described in any one of claims 3-8, in the preparation of a medicament for treating subsolid pulmonary nodules.

10. The application according to claim 9, characterized in that, The drug is used to treat subsolid pulmonary nodules caused by phlegm-dampness stagnation and heat syndrome.

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