A traditional Chinese medicine composition for preventing and treating hashimoto's thyroiditis and its complications, a preparation method and application thereof

Abstract

The application discloses a traditional Chinese medicine composition for preventing and treating Hashimoto's thyroiditis and complications (thyroid nodules and / or mammary gland hyperplasia), which is prepared from raw medicinal materials in the following proportions: 1-10 parts of ginseng, 1-15 parts of astragalus, 1-40 parts of fritillaria, 1-20 parts of prunella vulgaris, 1-20 parts of smilax, 1-18 parts of curcuma, and 1-19 parts of scutellaria. In addition, the application also discloses a preparation method and application of the traditional Chinese medicine composition. Clinical efficacy and pharmacological researches prove that the traditional Chinese medicine composition has multiple effects of clearing heat and resolving toxins, promoting blood circulation to remove blood stasis, and tonifying qi and invigorating the spleen, so that the purposes of dispersing thyroid nodules, reducing mammary gland hyperplasia, and improving Hashimoto's thyroiditis symptoms are achieved.

Description

Technical Field

[0001] This invention relates to a traditional Chinese medicine composition, and more particularly to a traditional Chinese medicine composition for the prevention and treatment of Hashimoto's thyroiditis and its complications (thyroid nodules and / or breast hyperplasia). Furthermore, this invention also relates to a method for preparing the traditional Chinese medicine composition and its applications. Background Technology

[0002] Hashimoto's thyroiditis (HT) is the most common type of autoimmune thyroid disease, accounting for 20%-30% of thyroid diseases. Thyroid nodules are also frequently present, with approximately 20%-30% of Hashimoto's thyroiditis patients also having thyroid nodules, especially in women, where the incidence of thyroid nodules and breast hyperplasia is higher. HT is most common in women aged 30-50, and the incidence of thyroid nodules increases with age, especially in those over 40. The incidence is significantly higher in women than in men, with a male-to-female ratio of approximately 1:5-10, possibly related to female hormone levels and immune system characteristics. Furthermore, the incidence of Hashimoto's thyroiditis is higher in areas with high iodine intake (such as coastal areas). Genetic factors play an important role in the pathogenesis of Hashimoto's thyroiditis, with a clear familial aggregation phenomenon. Breast hyperplasia is also common in women of reproductive age (25-45 years old), with a peak age of 35-40 years. There is a high degree of overlap between the two in terms of gender and age distribution. The detection rate of breast nodules in patients with Hashimoto's thyroiditis can reach over 40%, significantly higher than in the general population (2-3 times higher risk). While the prevalence of breast hyperplasia in the general female population is 70%-80%, patients with Hashimoto's thyroiditis may have an even higher risk due to endocrine-immune disorders.

[0003] Hashimoto's thyroiditis (HT) is an autoimmune disease. Patients typically develop anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TgAb), leading to chronic inflammation and destruction of thyroid tissue. When a large number of lymphocytes infiltrate the thyroid tissue, it eventually leads to hypothyroidism. If patients with Hashimoto's thyroiditis experience prolonged immune attack on their thyroid tissue, it may cause hyperplasia or degeneration of thyroid follicular epithelial cells, resulting in nodules. Nodules can be of various types, including proliferative nodules, colloid nodules, and cystic nodules; a small number may be malignant nodules (thyroid cancer). Early Hashimoto's thyroiditis may be asymptomatic, later presenting as hypothyroidism (such as fatigue, cold intolerance, weight gain, and dry skin). Even when thyroid nodules are present, most are asymptomatic; some patients may have a palpable neck mass, and a few may experience difficulty swallowing or hoarseness due to nodule compression. Western medicine has no effective treatment for Hashimoto's thyroiditis (HT) complicated by nodules. Early-stage HT is generally not treated with intervention. If thyroid dysfunction occurs, levothyroxine sodium (L-T4) is typically used. L-T4 is the first-line drug for Hashimoto's thyroiditis complicated by hypothyroidism, and it can improve thyroid function; in some patients, the nodules may shrink. For patients with large nodules, significant compressive symptoms, or suspected malignancy, partial or total thyroidectomy may be performed. Other treatments, such as selenium supplements and vitamin D, can regulate immune function and have a certain auxiliary effect in reducing antibody levels. Scientists have discovered a connection between the breast and thyroid gland. Both are regulated by the hypothalamic-pituitary-thyroid axis and are affected by estrogen levels. Many studies have shown that the correlation between thyroid and breast diseases mainly stems from hormone interactions (such as the thyroid hormone → prolactin / estrogen axis) and a shared immune inflammatory background. Therefore, thyroid dysfunction (such as hypothyroidism or hyperthyroidism) in Hashimoto's patients can affect the metabolism of hormones such as estrogen and prolactin. Furthermore, Hashimoto's patients have chronic immune abnormalities and elevated levels of pro-inflammatory factors (such as IL-6 and TNF-α) in their bodies, which may indirectly affect the breast tissue microenvironment through systemic inflammation.

[0004] Traditional Chinese medicine (TCM) considers Hashimoto's thyroiditis (HT) combined with thyroid nodules to fall under the category of "goiter," with causes often related to emotional distress, dietary imbalances, and unsuitable environment. The main pathogenesis involves liver qi stagnation, phlegm and blood stasis, and spleen and kidney yang deficiency, leading to the accumulation of qi, phlegm, and blood stasis in the neck, forming a goiter. Breast hyperplasia is closely related to the liver and spleen, with the main pathogenesis being liver qi stagnation and spleen deficiency, and the accumulation of phlegm and blood stasis; both are caused by emotional factors. Therefore, the concept of "treating different diseases with the same method" applies to the presentation of Hashimoto's thyroiditis combined with breast hyperplasia.

[0005] Currently, there are many traditional Chinese medicine (TCM) patents for Hashimoto's thyroiditis complicated with thyroid nodules, mainly focusing on TCM compositions with immunomodulatory, anti-inflammatory, swelling-reducing, and nodule-softening effects. This study is an improvement based on a previous patent application (patent application number: 202010950834.4), which consists of multiple herbs including Fritillaria cirrhosa, Smilax glabra, ginseng, and Prunella vulgaris. During the application of the previous patent (patent application number 202010950834.4), the following shortcomings were found: ① It has a good therapeutic effect only on Hashimoto's thyroiditis, but its effect on Hashimoto's thyroiditis complicated with thyroid nodules is generally limited. ② In cases of Hashimoto's thyroiditis complicated with thyroid nodules, female patients often also have breast hyperplasia. This formula cannot alleviate the symptoms of breast hyperplasia simultaneously. Currently, no existing TCM composition can simultaneously treat Hashimoto's thyroiditis complicated with thyroid nodules and breast hyperplasia. ③ The function of this formula in inhibiting thyroid immune damage still has room for improvement. Therefore, this patent improves and optimizes the previous patent, resulting in a significant improvement in the breadth of indications and therapeutic effects. Summary of the Invention

[0006] In order to overcome at least one deficiency in the prior art, the present invention provides a traditional Chinese medicine composition for the prevention and treatment of Hashimoto's thyroiditis and its complications, as well as its preparation method and application.

[0007] In one aspect of the present invention, a traditional Chinese medicine composition for preventing and treating Hashimoto's thyroiditis and its complications is provided, which is made from the following raw materials in parts by weight: ginseng 1-10 parts, astragalus 1-15 parts, fritillaria 1-40 parts, prunella vulgaris 1-20 parts, smilax china 1-20 parts, turmeric 1-18 parts, and scutellaria baicalensis 1-19 parts.

[0008] The preferred proportions of the above-mentioned raw materials are: ginseng 1-5 parts, astragalus 7-11 parts, fritillaria 27-33 parts, prunella vulgaris 12-18 parts, smilax china 12-18 parts, turmeric 8-12 parts, and scutellaria baicalensis 9-15 parts.

[0009] The preferred proportions of the above-mentioned raw materials are: ginseng 3-5 parts, astragalus 9-11 parts, fritillaria 30-33 parts, prunella vulgaris 15-18 parts, smilax china 15-18 parts, turmeric 10-12 parts, and scutellaria baicalensis 12-15 parts.

[0010] The preferred ratio of the above-mentioned raw materials is: 3 parts ginseng, 9 parts astragalus, 30 parts fritillaria, 15 parts prunella vulgaris, 15 parts smilax china, 10 parts turmeric, and 12 parts scutellaria baicalensis.

[0011] In other embodiments, the fritillaria is composed of Sichuan fritillaria and Zhejiang fritillaria in a 1:1 weight ratio, the turmeric is Guangyujin, and the above-mentioned complications are thyroid nodules and / or breast hyperplasia.

[0012] In another aspect, the present invention provides a method for preparing the above-mentioned traditional Chinese medicine composition, comprising the following steps:

[0013] S1: Weigh the raw materials according to the formula. First decoction: Add 9-11 times the amount of water to the herbs, soak for 1.5 hours, reflux and extract for 1-2 hours, and filter. Second decoction: Add 9-11 times the amount of water to the dregs, reflux and extract for 1-2 hours, and filter. Combine the two filtrates to obtain the extract.

[0014] S2: The extract is concentrated under reduced pressure at 60-80℃ and a vacuum degree of 0.02-0.08MPa to a relative density of 1.02-1.05 (measured at 60±2℃) to obtain the concentrated extract;

[0015] S3: Spray dry the concentrated extract with an inlet air temperature of 160-200℃, an injection speed of 20-30 rpm, and a preheating temperature of 80-95℃ to obtain the dry extract powder.

[0016] S4: Mix the dry powder with excipients, dry granulate and sizing to produce a medicine.

[0017] In other embodiments, the excipient in S4 is maltodextrin, and granulation is performed using a 10-mesh sieve and a 40-mesh sieve.

[0018] In another aspect, the present invention provides the use of the above-mentioned traditional Chinese medicine composition in the preparation of a medicament for treating Hashimoto's thyroiditis.

[0019] In another aspect, the present invention provides the use of the above-mentioned traditional Chinese medicine composition in the preparation of a medicament for treating Hashimoto's thyroiditis complicated with thyroid nodules and / or breast hyperplasia.

[0020] In other embodiments, the drug is in the form of granules, tablets, capsules, or oral liquid.

[0021] The traditional Chinese medicines used in this invention are effective, safe, and have significant therapeutic effects. Fritillaria is a general term for a class of perennial herbaceous plants belonging to the genus Fritillaria in the family Liliaceae. Its dried bulb is the core part of traditional Chinese medicine, including Sichuan Fritillaria, Zhejiang Fritillaria, and Ping Fritillaria. Sichuan Fritillaria moistens dryness, Zhejiang Fritillaria disperses nodules, and Ping Fritillaria resolves phlegm. In this invention, Sichuan Fritillaria and Zhejiang Fritillaria are preferred. Ginseng is the dried root and rhizome of Panax ginseng (family Araliaceae), possessing four core effects: greatly replenishing vital energy, tonifying the spleen and lungs, promoting body fluid production and calming the mind, and improving intelligence and anti-aging. Astragalus is the dried root of Astragalus membranaceus or Astragalus mongholicus (family Fabaceae), a commonly used clinical tonic with effects such as replenishing qi and raising yang, consolidating the exterior and stopping sweating, promoting diuresis and reducing swelling, and promoting tissue regeneration and detoxification. Prunella vulgaris is the plant Prunella vulgaris (family Lamiaceae). The dried fruit spikes of *Vulgaris*, harvested in summer when the spikes turn reddish-brown, have the core effects of clearing liver fire and dispersing stagnation; Smilax china is the dried rhizome of the lily family plant *Smilax china*, distinguished by its nodular protuberances and reddish-brown rings on the cross-section, and has the core effects of dispelling wind and dampness, detoxifying and dispersing blood stasis; Scutellaria baicalensis is the dried root of the lamiaceae family plant *Scutellaria baicalensis*, and has the core effects of clearing heat and drying dampness, purging fire and detoxifying; Curcuma longa is the ginger family plant *Curcuma wenyujin*, *Curcuma longa*, *Curcuma kwangsiensis*, or *Curcuma zedoaria*. The dried tuberous roots of turmeric (Phyrocaulis phaeocaulis) are harvested in winter after the stems and leaves have withered. After removing mud and fine roots, they are steamed or boiled until thoroughly cooked, then dried. They possess core medicinal properties of promoting blood circulation and relieving pain, regulating qi and relieving depression, clearing the heart and cooling the blood, and promoting bile secretion and reducing jaundice. Among these, the tuberous roots of turmeric (specifically, those of *Curcuma longa*) have a significantly higher curcumin content than other varieties, which is the material basis for their anti-inflammatory and hepatoprotective activities. In this invention, *Curcuma longa* is the preferred ingredient.

[0022] Traditional Chinese medicine (TCM) theory posits that the formula addresses liver stagnation and qi stagnation, resolves phlegm and nodules, invigorates blood circulation and removes blood stasis, and warms and tonifies the spleen and kidneys. Based on this TCM theory, the aforementioned herbal combination primarily uses Prunella vulgaris and Fritillaria cirrhosa to clear heat, resolve phlegm, and reduce swelling; ginseng and Astragalus membranaceus are used as adjuncts to tonify qi, strengthen the body's resistance, and promote blood circulation; Smilax glabra and Curcuma longa invigorate blood circulation, remove blood stasis, soothe the liver, and relieve depression; and Scutellaria baicalensis clears heat, detoxifies, and reduces swelling. Together, these herbs work to treat Hashimoto's thyroiditis complicated with thyroid nodules and breast hyperplasia, addressing both the local lesions and the overall qi and blood system, achieving a comprehensive cure. This formula embodies the principles of TCM syndrome differentiation and treatment, comprehensively addressing the key pathogenesis of Hashimoto's thyroiditis—deficiency of qi and yin, and the mutual binding of phlegm and blood stasis. The overall approach of this formula is to achieve the goals of dispersing thyroid nodules, reducing breast hyperplasia, and improving the symptoms of Hashimoto's thyroiditis through multiple actions such as clearing heat and detoxifying, invigorating blood circulation, removing blood stasis, and tonifying qi and strengthening the spleen.

[0023] The beneficial effects of this invention are: the above-mentioned traditional Chinese medicine composition further improves the inhibition of thyroid immune damage, has a good therapeutic effect on Hashimoto's thyroiditis complicated with thyroid nodules, has a clear and good therapeutic effect on Hashimoto's thyroiditis complicated with breast hyperplasia, and also has a clear and good therapeutic effect on Hashimoto's thyroiditis complicated with thyroid nodules and breast hyperplasia.

[0024] The following will further explain the concept, specific implementation methods and technical effects of the present invention, so as to fully understand the purpose, features and effects of the present invention. Detailed Implementation

[0025] The present invention will now be described with reference to specific embodiments. Unless otherwise specified in the present invention, the technical methods involved are all conventionally used by those skilled in the art and will not be described in detail here.

[0026] Example 1: Prescription Screening and Optimization

[0027] In our previous study, a traditional Chinese medicine composition consisting of 15g of Fritillaria cirrhosa, 15g of Smilax glabra, 9g of ginseng, and 15g of Prunella vulgaris showed good efficacy in treating Hashimoto's thyroiditis. This prescription also showed some effect in treating thyroid nodules. However, to screen for the most ideal drug for treating Hashimoto's thyroiditis complicated with thyroid nodules, we selected the human thyroid follicular epithelial cell lines Nthy-ori 3-1 and THP-1 to conduct a prescription screening study. The thyroid immune damage suppression experiment based on the THP-1 / Nthy-ori 3-1 co-culture model was specifically implemented as follows:

[0028] I. Experimental Methods

[0029] 1. Cell model construction:

[0030] (1) THP-1 cells were stimulated with 200 μg / L LPS for 24 hours to induce differentiation into macrophages.

[0031] (2) Activated THP-1 macrophages and Nthy-ori 3-1 thyroid cells were co-cultured at a ratio of 1:5 to simulate the in vivo immune attack environment.

[0032] 2. Experimental Groups:

[0033] (1) Normal group: Nthy-ori 3-1 cells cultured alone

[0034] (2) Model group: Nthy-ori 3-1 cells + LPS-activated macrophages

[0035] (3) Drug treatment group: The test drug (each herb and compound) was added to the model group at a final concentration of 5 μg / mL.

[0036] 3. Drug pretreatment:

[0037] (1) All drugs to be tested were pre-tested for cytotoxicity and their EC50 values ​​were selected;

[0038] (2) The activity screening uniformly adopted a final concentration of 5 μg / mL, drug intervention for 12 hours, and 6 replicates for each group.

[0039] 4. Testing indicators:

[0040] (1) Collect cell supernatant and detect the levels of thyroid peroxidase antibody (TPOAb), interleukin-6 (IL-6) and thyroxine (T4).

[0041] II. Experimental results are shown in Table 1

[0042] 1. Model Validation:

[0043] Compared with the normal group, the model group showed significantly increased levels of TPOAb and IL-6 (P<0.01) and significantly decreased levels of T4 (P<0.01), indicating that the immune injury model was successfully established.

[0044] 2. Effects of single medicinal herbs:

[0045] Compared with the model group, each single herb group (Astragalus membranaceus, Curcuma longa, Fritillaria cirrhosa, Smilax china, Panax ginseng, Prunella vulgaris, Scutellaria baicalensis) significantly reduced TPOAb and IL-6 levels (P<0.05 or P<0.01); among them, Astragalus membranaceus and Curcuma longa had the most significant effect on increasing T4 levels (P<0.01).

[0046] 3. Effects of compound combination:

[0047] (1) Four-ingredient compound (Fritillaria cirrhosa + Smilax china + Ginseng + Prunella vulgaris): TPOAb and IL-6 were significantly decreased (P<0.05 or P<0.01), and T4 level was significantly increased (P<0.01).

[0048] (2) Seven-ingredient compound (ginseng + astragalus + fritillaria + prunella vulgaris + smilax china + turmeric + scutellaria baicalensis): The effect was further enhanced compared with the four-ingredient compound. The inhibition rates of TPOAb and IL-6 were significantly increased (P<0.01), and the increase in T4 was extremely significant (P<0.01), indicating that the combination has a synergistic effect on improving thyroid function and regulating immune inflammation.

[0049] III. Conclusion

[0050] A seven-ingredient compound composed of ginseng, astragalus, fritillaria cirrhosa, prunella vulgaris, smilax china, turmeric, and scutellaria baicalensis can synergistically reduce thyroid autoantibodies (TPOAb), inhibit the release of inflammatory factors (IL-6), and significantly increase thyroid hormone (T4) levels, providing an effective candidate composition for the treatment of thyroid immune damage.

[0051] Table 1. Effects of single herbs or combinations of traditional Chinese medicine on thyroid antibodies, inflammation, and function (n=6)

[0052]

[0053] Note: When comparing with the normal group, 'a' indicates P < 0.01, and 'b' indicates P < 0.05.

[0054] The above experiments, using standardized cell models and a uniform drug concentration (5 μg / mL), verified the significant synergistic effect of the seven-herb compound in regulating thyroid function indicators (T4), autoimmune indicators (TPOAb), and inflammatory factors (IL-6). Its effect was superior to that of single herbs and the four-herb compound combination. Therefore, it can be seen that the traditional Chinese medicine composition of the present invention does have a clear therapeutic effect on Hashimoto's thyroiditis and thyroid nodules, and the therapeutic effect is significantly better than that of single herbs and the four-herb compound combination (Fritillaria cirrhosa, Smilax china, Ginseng, and Prunella vulgaris).

[0055] Example 2: Orthogonal Experiment for Prescription Optimization

[0056] To address the balance between the economy and efficacy of key medicinal materials in the compound prescription, this embodiment aims to clarify the following issues through orthogonal experimental design: The prices of ginseng and astragalus, both qi-tonifying herbs in the prescription, differ; can they be substituted? The dosage and price of fritillaria cirrhosa and fritillaria thunbergii also differ significantly; will their efficacy differ? Curcuma longa and scutellaria baicalensis have significant effects on improving thyroid function and nodules; their dosage also needs to be investigated. Since the dosages of prunella vulgaris (15g) and smilax china (15g) remain unchanged, we plan to design a three-factor, three-level orthogonal experiment to further optimize the prescription. The factors and levels are shown in Table 2.

[0057] Table 2 Factor and Level Design Table

[0058]

[0059] For a three-factor, three-level design, the commonly used orthogonal array is L9(3). 4This study included nine experimental groups, each representing a combination of factors and levels: A1B1C1, A1B2C2, A1B3C3, A2B1C2, A2B2C3, A2B3C1, A3B1C3, A3B2C1, and A3B3C2. Ten times the amount of each of the nine prescriptions was purchased and dried extracts were prepared using a conventional pre-boiling method. A co-culture method of thyroid cells and immune cells was used to screen for the optimal prescription based on differences in antibody indicators, thyroid function indicators, and inflammation levels, specifically TPOAb and IL-6 levels. The experimental results are shown in Table 3-1. The results of the screening of each combination are as follows. We selected TPOAb and IL-6 levels, which characterize thyroid function, as the main effect indicators for prescription screening. Lower values ​​for both TPOAb and IL-6 were preferred. The total score normalization method was used, with the lowest possible value being the OD value. i =(y max -y i ) / (y max -y min The two factors are weighted using a value OD = 0.6y1. i +0.4y2 i By calculating the average values ​​of each factor, range analysis showed that the influence strength of factors was: A>C>B (see Table 3-2). The mean OD values ​​of the interactive combination results were: A2×B2 = 0.976, A3×C3 = 0.872, and B2×C3 = 0.845. The combination A2B2C3 showed a significant synergistic effect (theoretical value 0.976 > the sum of the independent factors 0.590+0.636+0.713=1.939 / 3=0.646). Analysis of variance showed that factor A had a highly significant effect on the OD value (F=28.44, P<0.001), and the A×B interaction was significant (P=0.038), suggesting a synergistic effect between Fritillaria cirrhosa and Curcuma longa + Scutellaria baicalensis. The optimal parameter combination is A2B2C3, which consists of 15g of Fritillaria cirrhosa, 15g of Fritillaria thunbergii, 15g of Prunella vulgaris, 10g of Curcuma longa, 5g of Smilax china, 12g of Scutellaria baicalensis, 3g of Panax ginseng, and 9g of Astragalus membranaceus, resulting in the best compound effect.

[0060] Table 3-1 Results of the three-factor, three-level screening

[0061] Serial Number Group TPOAb (IU / mL) IL-6 (pg / mL) TPOAb IL-6 OD value 1 A1B1C1 120.12 320.28 0.00 0.15 0.06 2 A1B2C2 109.21 299.14 0.37 0.340 0.358 3 A1B3C3 115.24 309.15 0.17 0.251 0.202 4 A2B1C2 102.19 266.9 0.61 0.627 0.618 5 A2B2C3 91.85 224.92 0.96 1.000 0.976 6 A2B3C1 111.54 337.4 0.29 0.000 0.174 7 A3B1C3 90.78 236.57 1.00 0.896 0.960 8 A3B2C1 104.18 267.58 0.54 0.621 0.572 9 A3B3C2 96.7 251.88 0.80 0.760 0.784

[0062] Note: Therefore, the data is the average of 6 replicates. TPOAb max =120.12, TPOAb min =90.78; IL-6 max =337.40, IL-6 min =224.92

[0063] Table 3-2 Factor Levels and Ranges

[0064]

[0065]

[0066] Example 3: Preparation of the Composition Extract and Granules

[0067] Raw material ratio: Take 3kg of ginseng, 9kg of astragalus, 30kg of fritillaria (15kg of Sichuan fritillaria and 15kg of Zhejiang fritillaria), 15kg of prunella vulgaris, 15kg of smilax china, 10kg of turmeric, and 12kg of scutellaria baicalensis, for a total of 94kg of Chinese medicinal herbs.

[0068] Preparation method

[0069] S1: Extraction: First decoction: Add 10 times the amount of water (940L) to the medicinal materials, soak for 1.5 hours, reflux extract at a gentle boil for 1.5 hours, and filter; Second decoction: Add 10 times the amount of water (940L) to the dregs, reflux extract at a gentle boil for 1.5 hours, and filter; Combine the two filtrates to obtain the extract;

[0070] S2: Concentration: The extract is concentrated under reduced pressure at 60-80℃ and 0.02-0.08MPa; concentrated to a relative density of 1.02-1.05 (60±2℃) to obtain concentrated clear extract (dry extract rate 16%-22%).

[0071] S3: Drying: The extract is spray-dried (the liquid is preheated to 90°C, the air inlet temperature is 160-200°C, and the injection speed is 20-30 rpm); 15.1 kg of dry extract powder is obtained (code JB);

[0072] S4: Granulation: Mix dry powder with an appropriate amount of maltodextrin; shape by dry granulation machine, and granulate by 10-mesh and 40-mesh sieves; obtain granules (code JBKL), packaged as 12g / bag.

[0073] Effects of Example 4 on a rat model of nodular goiter

[0074] Male SD rats, weighing 120-140g, were selected and housed in an SFP-grade laboratory at a temperature of 25±2℃ and a humidity of 60±5%. The lighting system typically used a 12-hour light / 12-hour dark cycle to maintain the animals' circadian rhythms. Standard feed and drinking water were provided daily, and bedding was changed weekly for sterilization. Modeling was initiated after two weeks of environmental acclimatization. The normal control group (n=10) was administered 1ml / 100g body weight of physiological saline daily, while the remaining rats were administered 1ml / 100g body weight of a 0.1% propylthiouracil (PTU) solution once daily in the morning for 8 weeks. After model establishment, color Doppler ultrasound was used to determine the success of the model in each group, and 50 rats with successful models were selected. After being numbered, the model animals were randomly divided into groups of 10 each: the model control group (Model group), the high-dose dry extract powder group (JB-H group, dose of 14.44 g / kg (equivalent to raw medicinal material)), the medium-dose dry extract powder group (JB-M group, dose of 7.22 g / kg (equivalent to raw medicinal material)), the low-dose dry extract powder group (JB-L group, dose of 3.61 g / kg (equivalent to raw medicinal material)), and the levothyroxine sodium tablet group (L-T4 group).

[0075] Drug administration began in week 9. The L-T4 group was administered 1 ml / 100g body weight of 0.1 mg / L L-T4 solution by gavage; the drug-treated groups were given the same doses as JB-H, JB-M, and JB-L, respectively; the Model and normal groups were administered 1 ml / 100g body weight of distilled water by gavage. All groups were administered the drug once daily at 8:00 AM for 8 consecutive weeks. After drug administration, rats were anesthetized by intraperitoneal injection of 2% sodium pentobarbital (3 mL / kg). After successful anesthesia, blood was collected from the abdominal aorta. The neck skin was then incised to expose the trachea, and the thyroid gland tissue on both sides was located and completely separated, removing muscles and other tissues. A portion of the right thyroid gland from each rat was removed and placed in a 1.5 ml EP tube, which was stored at -20°C for later use. Statistical analysis was performed using SPSS 27.0 software. Quantitative data were expressed as mean ± standard deviation (x ± s). One-way ANOVA was used for comparisons among multiple groups, and LSD method was used for pairwise comparisons. P < 0.05 was considered statistically significant.

[0076] (1) Effect of JB composition (i.e., the dry powder obtained in S3 of Example 3) on thyroid weight

[0077] Compared with the normal group, the thyroid gland weight and relative weight of rats in the Model group were 158.37±27.23 mg, with a relative increase of 0.375±0.071‰ (P<0.01). Compared with the Model group, the thyroid gland weight of the L-T4 group was 98.45±14.37 mg, with a relative decrease of 0.228±0.015‰ (P<0.01). Compared with the Model group, the thyroid gland weight of the JB-H group was 101.37±16.26 mg, with a relative decrease of 0.248±0.024‰ (P<0.01). Moreover, compared with the Model group, the thyroid gland weight of the JB-M group was 112.34±20.19 mg, with a relative decrease of 0.273±0.062‰ (P<0.01). Therefore, JB (i.e., the traditional Chinese medicine composition of this invention) can significantly reduce the weight of the thyroid gland. Detailed data are shown in Table 4.

[0078] Table 4. Effects of different groups on thyroid mass and relative mass (n=10, mean±SD)

[0079] Group Body weight (g) Thyroid mass (mg) Relative weight (‰) normal group 586.19±46.36 87.23±20.22 0.148±0.009 Model Group 421.60±28.96** 158.37±27.23** 0.375±0.071** L-T4 Group 429.01±36.25 <![CDATA[98.45±14.37 ## ]]> <![CDATA[0.228±0.015 ## ]]> JB-H Group 407.95±9.96 <![CDATA[101.37±16.26 ## ]]> <![CDATA[0.248±0.024 ## ]]> JB-M Group 411.08±29.42 <![CDATA[112.34±20.19 ## ]]> <![CDATA[0.273±0.062 ## ]]> JB-L Group 420.20±26.38 141.38±32.28 0.336±0.089

[0080] Note: This indicates a highly statistically significant difference compared to the normal group (P<0.01); ** This indicates that the difference is statistically significant compared to the normal group; ## This indicates that the difference compared with the model group was statistically significant (P<0.01).

[0081] (2) Effects of JB composition (i.e., the dry powder obtained in S3 of Example 3) on thyroid function

[0082] The results of serum thyroid function index studies showed that, compared with the normal group, the serum TSH level in the Model group rats was significantly increased to 4.81±0.77 μIU / L (P<0.05), while the FT3 and FT4 levels were significantly decreased to 5.29±0.39 pmol / L (P<0.01) and 7.19±0.50 pmol / L, respectively. Compared with the Model group, the serum TSH level in the L-T4 group, LH-H group, and LH-M group rats was significantly decreased (P<0.05 or P<0.01); the FT3 and FT4 levels were significantly increased, which was statistically significant (P<0.01), indicating that JB (i.e., the traditional Chinese medicine composition of this invention) can effectively improve thyroid function in rats with nodular thyroid disease. Detailed data are shown in Table 5.

[0083] Table 5. Effects of different groups on thyroid function (n=10, mean±SD)

[0084]

[0085] Note: Compared with the Model group, a represents P<0.05 and b represents P<0.01.

[0086] (3) Effects of JB composition (i.e., the dry powder obtained in S3 of Example 3) on the thyroid gland

[0087] Ultrasound examination showed that the anteroposterior and medial-lateral diameters of the thyroid gland in the model group rats were significantly larger than those in the normal group. Simultaneously, the model group rats exhibited asymmetrical enlargement of the gland, with nodules on the lateral lobes of the thyroid gland lacking capsules, having indistinct and irregular borders, and scattered punctate or linear fibrous hyperplasia with strong echoes. Furthermore, compared with the normal group, the volume of both thyroid lobes in the model group rats was significantly increased (P<0.01), reaching 35.1±2.67 mm. 3 and 32.11±2.65mm 3 The L-T4 group showed a significant decrease in bilateral goiter (P<0.01). Furthermore, the left and right thyroid volumes in the JB-H, JB-M, and JB-L groups all decreased significantly (P<0.05 or P<0.01). Additionally, ultrasound examination showed a significant reduction in some small nodules in the JB-H and JB-M groups. These results indicate that JB (i.e., the traditional Chinese medicine composition of this invention) can significantly improve goiter and significantly reduce some small nodules. Detailed data are shown in Table 6.

[0088] Table 6. Effects of different groups on bilateral thyroid volume (n=10, mean±SD)

[0089] Group <![CDATA[Left side (mm 3 )]]> <![CDATA[Right side (mm 3 )]]> normal group <![CDATA[12.13±3.28 b ]]> <![CDATA[11.22±2.72 b <!-- 8 -->]]> Model Group 35.1±2.67 32.11±2.65 L-T4 Group <![CDATA[23.12±3.82 b ]]> <![CDATA[19.18±4.23 b ]]> JB-H Group <![CDATA[19.11±3.47 b ]]> <![CDATA[18.11±3.17 b ]]> JB-M Group <![CDATA[23.21±3.78 b ]]> <![CDATA[22.76±3.89 b ]]> JB-L Group <![CDATA[27.87±3.88 a ]]> <![CDATA[26.13±3.19 a ]]>

[0090] Note: Compared with the control group, a indicates P < 0.01, b indicates P < 0.05.

[0091] (4) Effects of JB composition (i.e., the dry powder obtained in S3 of Example 3) on thyroid pathology

[0092] Pathological observation and examination of thyroid tissue revealed that, in the model group, HE staining of thyroid sections showed that the follicles in the thyroid tissue of the normal group rats were regularly arranged, uniform in size, and mostly spherical or oval, with no inflammatory cell infiltration in the stroma. In contrast, the thyroid tissue of the model group exhibited irregular shape and follicle size with significant variations, and showed marked epithelial cell proliferation, disordered arrangement, and colloid compression and uneven distribution. In the L-T4, JB-H, and JB-M groups, thyroid tissue follicle swelling was reduced, with minimal peripheral hyperplasia, decreased internal papillary structures, and a more regular arrangement of epithelial cells. The JB-H group rats showed significant improvement in thyroid epithelial cell swelling and interstitial inflammatory cell infiltration.

[0093] Based on the above experimental data, the traditional Chinese medicine composition of the present invention has the following comprehensive therapeutic effects on rats with a propylthiouracil-induced nodular goiter model:

[0094] Thyroid weight regulation: Compared with the model group (thyroid weight 158.37±27.23 mg, relative weight 0.375±0.071‰), the thyroid weight in the high-dose group (JB-H group) was significantly reduced to 101.37±16.26 mg (P<0.01), and the relative weight decreased to 0.248±0.024‰ (P<0.01); the thyroid weight in the medium-dose group (JB-M group) decreased to 112.34±20.19 mg (P<0.01), and the relative weight decreased to 0.273±0.062‰ (P<0.01).

[0095] Recovery of thyroid function: In the model group, serum TSH increased to 4.81±0.77 μIU / L, while FT3 and FT4 decreased to 5.29±0.39 pmol / L and 7.19±0.50 pmol / L, respectively. In the JB-H group, TSH decreased to 3.39±0.73 μIU / L (P<0.01), FT3 increased to 6.66±0.80 pmol / L (P<0.01), and FT4 increased to 10.15±0.49 pmol / L (P<0.01); in the JB-M group, TSH decreased to 3.41±1.22 μIU / L (P<0.01), and FT4 increased to 9.85±0.85 pmol / L (P<0.01).

[0096] Improvement in thyroid volume and structure: Ultrasound examination showed a significant increase in bilateral thyroid volume in the model group (left 35.1±2.67mm). 3 32.11±2.65mm on the right side 3 The bilateral volume was significantly reduced in the JB-H group (left side 19.11±3.47mm). 3 The right side measures 18.11 ± 3.17 mm. 3 (P<0.01), and the number of small nodules decreased; in the JB-M group, the left side decreased to 23.21±3.78mm. 3 (P<0.01), the right side decreased to 22.76±3.89mm. 3 (P<0.01).

[0097] Pathological and histological repair: In the model group, thyroid follicles showed uneven size, disordered epithelial cell proliferation, and abnormal colloid distribution. In the JB-H and JB-M groups, thyroid follicle swelling was reduced, epithelial cell arrangement became more regular, and inflammatory infiltration was significantly improved, with the pathological repair effect being particularly significant in the JB-H group.

[0098] Conclusion: The traditional Chinese medicine composition of the present invention significantly reduces thyroid mass and volume (P<0.01), restores serum TSH, FT3 and FT4 to normal levels (P<0.01), and improves thyroid follicular structure disorder and inflammatory infiltration, comprehensively demonstrating that it has a clear therapeutic effect on Hashimoto's thyroiditis complicated with thyroid nodules.

[0099] Example 5: Clinical observation of Hashimoto's thyroiditis complicated with thyroid nodules according to the present invention.

[0100] To clarify the clinical efficacy of the traditional Chinese medicine composition of the present invention, a single-center, randomized, double-blind, controlled clinical trial design was adopted. Eighty patients diagnosed with Hashimoto's thyroiditis complicated with thyroid nodules and diagnosed by traditional Chinese medicine as having qi deficiency and phlegm stasis were selected as the observation subjects. They were randomly divided into a control group and an observation group of 40 patients each using a random number table. The treatment course was 24 weeks.

[0101] (1) Western medicine diagnostic criteria, formulated with reference to "Internal Medicine" and the 2008 "Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China", mainly manifested as positive serum thyroid peroxidase antibody (TPOAb) and / or thyroglobulin antibody (TGAb) in thyroid autoantibody testing. Thyroid ultrasound examination showed diffuse heterogeneous changes in the thyroid gland, or with thickening of the isthmus, heterogeneous echo areas of varying degrees and thyroid nodules, and the ultrasound findings did not support malignant nodules.

[0102] (2) Diagnostic criteria for TCM syndromes: Based on the descriptions of goiter and qi deficiency with phlegm stasis in "Internal Medicine of Traditional Chinese Medicine", "Guiding Principles for Clinical Research of New Chinese Herbal Drugs", and "Surgery of Traditional Chinese Medicine", the following criteria are established: ① Primary symptom: A hard mass in the front of the neck, with a smooth surface and a nodular feel, which moves up and down with swallowing. The nodule persists for a long time and is asymptomatic or accompanied by neck discomfort. ② Secondary symptoms: Fatigue, shortness of breath, reluctance to speak, anxiety, chest tightness, poor appetite, constipation or loose stools, etc. Tongue appearance: Pale or red tongue with a thin coating (thin white or thin yellow) or no coating. Pulse appearance: Deep and wiry or deep and hesitant pulse. If all primary symptoms and one or more secondary symptoms are present, the diagnosis can be made by referring to the tongue and pulse appearance.

[0103] (4) Inclusion criteria for case selection: ① Patients meeting the diagnostic criteria for Hashimoto's thyroiditis with nodules. ② Patients whose TCM syndrome differentiation belongs to the Qi deficiency and phlegm stasis type and who are female. ③ Thyroid nodules detected by ultrasound are solid, cystic, or calcified. ④ TSH, FT3, and FT4 values ​​are within the normal range. ⑤ Patients are between 18 and 60 years old. ⑥ Patients are willing to accept observation and have the conditions to complete the process.

[0104] (5) Exclusion criteria: 1) Concurrent hypothyroidism or subclinical hypothyroidism; 2) Concurrent thyroid nodules with ultrasound examination indicating C-TIRADS category 4A or above; 3) Concurrent thyroid diseases, such as primary hyperthyroidism, Graves' disease, thyrotoxicosis, subacute thyroiditis, thyroid lymphoma, or thyroid malignancy; 4) Those who have received immunomodulatory agents, selenium preparations, traditional Chinese medicine interventions, or other drugs that affect efficacy evaluation within the past month for any reason, or those who have participated in any clinical trial (enrolled and used the investigational drug) within the past 3 months; 5) History of previous thyroid radioactive iodine therapy or surgery; 6) Concurrent other malignant tumors; 7) Concurrent severe heart disease. Patients with diseases of the brain, liver, kidneys, digestive tract, or blood system; ALT and AST > 1.5 times the upper limit of the normal reference range; serum creatinine > the upper limit of the normal reference range; 8) Patients with mental or neurological diseases who cannot take medication on time or who abuse drugs or other substances; 9) Patients with other serious autoimmune diseases who have received immunomodulatory therapy within 3 months, including but not limited to type I diabetes, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, inflammatory bowel disease, autoimmune adrenocortical insufficiency, systemic lupus erythematosus, etc.; 10) Pregnant or lactating women, or those who plan to become pregnant in the near future; 11) Patients with known or suspected allergies to the investigational drug; 12) Patients deemed unsuitable for clinical trials by researchers for other reasons.

[0105] (6) Prohibited medications: During the entire trial period, in addition to the study drug, the following Chinese medicines, Western medicines and related therapies that may affect the efficacy of the drug are prohibited: ① Western medicines that interfere with the efficacy of the disease, such as selenium preparations, glucocorticoids, and statins; ② Chinese medicine compound prescriptions and their preparations used to improve thyroid inflammation and function, such as modified Chaihu Shugan San, modified Xiaoyao San, modified Zhizi Qinggan Tang, and modified Haizao Yuhu, are not allowed during the trial period; ③ Thyroid hormone replacement drugs.

[0106] (7) Withdrawal (dropout) criteria: ① Serious adverse events occur; ② Poor subject compliance; ③ Subject is pregnant or planning to become pregnant; ④ Subject participates in any other clinical drug clinical trial during the study period, or participates in any medical research that is scientifically or medically conflicting with this study.

[0107] (8) Treatment methods and administration cycle

[0108] Observation group: The granules (JBKL) prepared in part of Example 3 were administered orally, one sachet at a time, twice a day, for 24 consecutive weeks.

[0109] Control group: "JB mimic granules" (containing 1% JB extract) (JB-SIM) were administered orally, one sachet at a time, twice a day, for 24 consecutive weeks.

[0110] Treatment consisted of 24 weeks as one course, with a total of one course of observation. Thyroid function tests, thyroid autoantibodies, and thyroid color Doppler ultrasound were performed before treatment, and at 12 and 24 weeks after treatment, respectively. The results of the examinations and TCM syndrome scores were recorded before and after treatment.

[0111] (9) Observation indicators

[0112] 1) Main therapeutic indicators

[0113] After 24 weeks of treatment, 50% of the subjects achieved a decrease in anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) titers. Thyroid nodule diameter was assessed using color Doppler ultrasound. If multiple nodules were present, the largest diameter of the largest nodule was recorded. Thyroid nodule diameters were recorded before and after treatment.

[0114] 2) Secondary efficacy indicators

[0115] ① Changes in TPOAb and TgAb titers in subjects from baseline after 12 and 24 weeks of treatment;

[0116] ② Changes in the levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) in the subjects after 12 and 24 weeks of treatment compared to baseline;

[0117] ③ After 12 and 24 weeks of treatment, the changes in the subjects' TCM syndrome scores from baseline and the efficacy were recorded. The TCM syndrome score scale was developed with reference to the "TCM Syndrome Score Scale" and relevant clinical observation literature on Hashimoto's thyroiditis. The TCM syndrome scores were recorded and calculated for both groups of patients. The TCM syndrome score is the sum of the scores of each symptom and the total score.

[0118] (10) Statistical methods

[0119] All data were analyzed using professional statistical software. Quantitative data were described statistically as mean ± standard deviation. If the data followed a normal distribution and had homogeneous variances, paired-samples t-tests were used to assess the significance of efficacy differences before and after treatment. Categorical data were expressed as percentages, and chi-square tests were used for comparisons between two groups. If the data did not conform to a normal distribution, results were expressed as interquartile ranges (Median(Q1, Q3)) and Wilcoxon rank-sum tests were used. A p-value > 0.05 was considered statistically significant, and a p-value < 0.05 was considered statistically significant.

[0120] (11) Research completion

[0121] 1) General Information

[0122] In this clinical study, patient compliance was good, and no adverse reactions occurred during treatment. A total of 80 patients were enrolled, and none dropped out. All selected patients were female. The mean age in the observation group was 43.78 ± 8.26 years, and the mean age in the control group was 42.16 ± 8.26 years. There was no significant difference in age between the two groups (P>0.05), indicating that the two groups were comparable.

[0123] 2) Thyroid function

[0124] The results showed that the thyroid function of patients in both the observation group and the control group was within the normal range before and after treatment. The levels of triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) before and after treatment were normally distributed according to the normality test. The paired t-test showed no statistically significant difference between the pre- and post-treatment data (P > 0.05), indicating that the thyroid function of the patients selected in this clinical observation did not change after JBKL treatment. The data are detailed in Table 7.

[0125] Table 7. Effects of different treatment groups on thyroid function (n=40, mean±SD)

[0126]

[0127]

[0128] 3) Effects on thyroid antibodies

[0129] After JBKL treatment, the levels of anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) in the observation group significantly decreased. Before treatment, TGAb and TPOAb were 729.11±118.12 IU / mL and 436.34±122.12 IU / mL, respectively; after 12 weeks of treatment, they decreased to 321.12±50.12 IU / mL and 267.76±64.56 IU / mL, respectively. Paired t-tests showed a significant decrease before and after treatment. The decrease in TGAb and TPOAb levels was statistically significant (P<0.01), and the decrease was also statistically significant compared with the control group (P<0.01). After 24 weeks of treatment, TGAb and TPOAb levels decreased to 120.11±20.11 IU / mL and 89.13±17.94 IU / mL, respectively. Paired t-tests showed statistically significant decreases before and after treatment (P<0.01), and the decreases in both TGAb and TPOAb were statistically significant compared with the observation group (P<0.01). This suggests that the traditional Chinese medicine composition of this patent significantly reduces the levels of thyroid autoantibodies in patients with TGAb and TPOAb. Detailed data are shown in Table 8.

[0130] Table 8. Effects of different treatment groups on thyroid autoantibodies (n=40, mean±SD)

[0131]

[0132] Note: This indicates that the observation group showed a statistically significant difference compared to the pre-treatment group (P<0.01) according to the paired t-test. ## This indicates that, compared with the control group after treatment, there was a statistically significant difference (P<0.01) according to the paired t-test.

[0133] 4) Effects on thyroid nodules

[0134] In the observation group, after treatment with JBKL, the diameter of the thyroid nodules decreased. Before treatment, the diameter of the thyroid nodules was 12.11±3.56 mm, and after 12 weeks of treatment, the diameter decreased to 8.53±2.11 mm. A paired t-test showed a statistically significant difference between the pre- and post-treatment diameters (P<0.01). After 24 weeks of treatment, the diameter decreased to 6.33±1.38 mm, again showing a statistically significant difference (P<0.01). In contrast, the diameter of the thyroid nodules in the control group did not change significantly after treatment. This indicates that after 24 weeks of treatment with the traditional Chinese medicine composition of this invention, the diameter of the thyroid nodules can be significantly reduced. Detailed data are shown in Table 9.

[0135] Table 9. Effects of different treatment groups on thyroid nodules (n=40, mean±SD)

[0136]

[0137] Note: This indicates that the observation group showed a statistically significant difference compared to the pre-treatment group (P<0.01) according to the paired t-test. ## The results showed that, after treatment, the observation group and the control group had a statistically significant difference (P<0.01) according to the paired t-test.

[0138] In addition, by statistically analyzing the diameter data of thyroid nodules before and after treatment, and based on the criteria for judging the efficacy of thyroid nodule treatment: ① Marked effect: Thyroid ultrasound examination shows that the diameter of the thyroid nodule after treatment is 1 / 2 or more smaller than that before treatment. ② Effective: Thyroid ultrasound examination shows that the diameter of the thyroid nodule after treatment is reduced by 1 / 3, but less than 1 / 2 smaller than that before treatment. ③ Ineffective: Thyroid ultrasound examination shows that the diameter of the thyroid nodule after treatment is reduced by less than 1 / 3, or even increased in size. Note: Calculation formula: (Diameter of nodule before treatment - Diameter of nodule after treatment) / Diameter of nodule before treatment × 100%. The total effective rate calculated after 24 weeks of JBKL treatment was 67.5%, while the total effective rate of the control group was 7.5%. Detailed data are shown in Table 10.

[0139] Table 10. Effectiveness of different treatment groups in the treatment of thyroid nodules

[0140]

[0141]

[0142] 5) Impact on TCM syndromes

[0143] The total TCM syndrome score showed significant improvement. At baseline, the total TCM syndrome score was 14.57±6.37. After 12 weeks of JBKL treatment, the total TCM syndrome score decreased to 9.68±4.35. The paired t-test before and after treatment showed a statistically significant difference (P<0.01), and it was also statistically significant compared to the control group (P<0.01). After 24 weeks of treatment, the total TCM syndrome score decreased to 4.68±3.12. The paired t-test before and after treatment showed a statistically significant difference (P<0.01), and it was also statistically significant compared to the control group (P<0.01). The results indicate that the TCM composition of this invention has a significant effect on improving TCM syndromes. Detailed data are shown in Table 11.

[0144] Table 11 Effects of the observation group and the control group on TCM syndrome scores (n=40, mean±SD)

[0145]

[0146] Note: This indicates a statistically significant difference compared to before treatment, as determined by a paired t-test (P<0.01). ## This indicates that, compared with the control group after treatment, there was a statistically significant difference (P<0.01) according to the paired t-test.

[0147] Therefore, it is evident that the traditional Chinese medicine composition of this invention has a clear therapeutic effect on Hashimoto's thyroiditis complicated with thyroid nodules. This traditional Chinese medicine composition, through a multi-target regulatory mechanism, possesses the following characteristics:

[0148] ①Immune regulation (significantly reduces TPOAb / TgAb);

[0149] ② Anti-nodular hyperplasia (reducing the diameter of thyroid nodules);

[0150] ③ It has a triple effect of improving TCM syndrome (relieving symptoms of Qi deficiency and phlegm stasis), without disrupting the balance of thyroid function, and has outstanding safety, thus solving the clinical pain point of lacking effective TCM treatment for Hashimoto's thyroiditis complicated with thyroid nodules.

[0151] Example 6: Clinical observation of Hashimoto's thyroiditis complicated with breast hyperplasia according to the present invention.

[0152] To clarify the clinical efficacy of the traditional Chinese medicine composition of the present invention in treating Hashimoto's thyroiditis complicated with breast hyperplasia, a single-center, randomized, double-blind, controlled clinical trial design was adopted. Sixty patients diagnosed with Hashimoto's thyroiditis complicated with thyroid nodules, and whose TCM syndrome differentiation was Qi stagnation and phlegm-stasis type, were selected as the observation subjects. They were randomly divided into a control group and an observation group of 30 patients each using a random number table. The treatment course was 24 weeks.

[0153] (1) Western medicine diagnostic criteria

[0154] Diagnosis of Hashimoto's thyroiditis: Based on the "Internal Medicine" and the 2008 "Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China", the main manifestation is that the serum thyroid peroxidase antibody (TPOAb) and / or thyroglobulin antibody (TGAb) are positive in the thyroid autoantibody test.

[0155] Diagnosis of breast hyperplasia: Based on the 2016 edition of the "Expert Consensus on the Diagnosis and Treatment of Breast Hyperplasia" issued by the Women's Health Branch of the Chinese Preventive Medicine Association.

[0156] 1) Clinical symptoms: Cyclic pain (throbbing, stabbing or dull pain) in one or both breasts, which may radiate to the chest, ribs and back. The degree of pain is related to the menstrual cycle or emotional fluctuations, and the course of the disease is ≥3 months (continuous or intermittent cumulative).

[0157] 2) Physical signs: single / multiple nodules can be palpated. The nodules are diverse in shape, have indistinct borders, are not adherent to the skin or deep tissues, have good mobility, and their size can vary with the menstrual cycle or emotional changes.

[0158] 3) Exclusion criteria: Exclude precocious puberty (before Tanner stage II), gynecomastia, and benign or malignant breast tumors (which require pathological confirmation).

[0159] 4) Imaging evidence: malignancy is ruled out by breast ultrasound (BI-RADS classification ≤3) or mammography (ACR appropriateness criteria).

[0160] (2) The TCM diagnostic criteria (Qi stagnation and phlegm stasis syndrome) shall be implemented in accordance with the "Guiding Principles for Clinical Research of New Chinese Medicines (Trial)": (1) Primary symptoms: breast pain with periodic nodular changes, tightness in the neck, phlegm stagnation in the throat, and depression. (2) Secondary symptoms: hypochondriac pain (migratory), poor appetite, frequent sighing, and significant mood swings. (3) Tongue and pulse characteristics: red / pale red tongue, thin yellow or slightly greasy coating, and wiry / slippery pulse. The diagnosis shall meet the following conditions: primary symptoms ≥3 items; secondary symptoms ≥2 items; combined with characteristic tongue and pulse manifestations.

[0161] (3) Inclusion criteria for subjects

[0162] 1) Core inclusion criteria: Patients must meet the diagnostic criteria outlined in *Internal Medicine* and the 2008 *Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China*. Furthermore, the diagnosis must conform to the *Expert Consensus on the Diagnosis and Treatment of Breast Hyperplasia* (2016) and the TCM diagnostic criteria for Qi stagnation and phlegm stasis syndrome (referring to the ICD-11 Traditional Medicine module); the disease duration must be ≥3 months and the patient must be in the active phase (VAS pain score ≥4 points); the patient must be a woman of childbearing age (20-50 years old) and not pregnant / lactating.

[0163] 2) Compliance requirements: Voluntarily sign the informed consent form and promise to complete all follow-up milestones; complete baseline data (including imaging, laboratory and TCM four diagnostic records).

[0164] 3) Exclusion criteria for subjects

[0165] Disease-related exclusions: History of thyroid diseases such as hyperthyroidism / hypothyroidism, subacute thyroiditis, etc.; presence of breast space-occupying lesions (BI-RADS ≥ 4) or suspected malignant transformation tendency (such as calcifications, abnormal blood supply); presence of severe heart, liver, or kidney dysfunction (Child-Pugh C or eGFR < 30 mL / min) or endocrine and metabolic diseases such as diabetes or pituitary tumors.

[0166] Physiological exclusion: positive pregnancy test or breastfeeding women; known history of allergies or allergic constitution (involving the components of the study drug).

[0167] Exclusion factors for study confounding factors: receipt of hormone replacement therapy or immunomodulatory agents within the past 3 months; presence of mental disorders (DSM-V diagnostic criteria) or cognitive impairment (MMSE <24 points), which may affect study compliance.

[0168] (4) Treatment methods

[0169] Observation group: The granules (JBKL) prepared in Example 3 were administered orally, one sachet at a time, twice a day, for 24 consecutive weeks.

[0170] Control group: "JB mimic granules" (containing 1% JB extract) (JB-SIM) were administered orally, one sachet at a time, twice a day, for 24 consecutive weeks.

[0171] The treatment methods were the same for both groups, including psychological counseling, emotional regulation, avoiding spicy and stimulating foods, appropriate exercise, and avoiding overwork.

[0172] Treatment consisted of 24 weeks as one course, with a total of one course of observation. Thyroid function tests, thyroid autoantibodies, thyroid color Doppler ultrasound, and breast color Doppler ultrasound were performed before treatment, and at 12 and 24 weeks after treatment, respectively. The examination results and TCM syndrome scores were recorded before and after treatment.

[0173] (5) Observation indicators and methods

[0174] 1) Evaluation of therapeutic effect

[0175] Clinical efficacy was determined according to the relevant provisions of the "Guiding Principles for Clinical Research of New Traditional Chinese Medicines". ① Marked effect: Clinical symptoms significantly improved or basically disappeared, or improved by more than 30% compared with before treatment; ② Effective: Clinical symptoms improved to some extent, or improved by 10% to 29% compared with before treatment; ③ Ineffective: Clinical symptoms did not improve significantly, or the condition further developed or even worsened.

[0176] 2) Main observation indicators: ① Thyroid antibodies (TPOAb, TgAb) and thyroid function (TT3, TT4, FT3, FT4, TSH) were measured in both groups before and after treatment. ② Breast elastography was performed 7 days after menstruation ended before and after treatment to assess breast pain and lumps (the size of the breast lump was taken as the diameter of the largest lump). The evaluation criteria for the treatment efficacy of breast hyperplasia are shown in Table 12.

[0177] Table 12 Evaluation Criteria for the Treatment of Breast Hyperplasia

[0178]

[0179] 3) Safety assessment: blood routine, urine routine, liver function, electrocardiogram, etc. before and after treatment, and whether there is nausea, vomiting, abdominal pain, diarrhea, etc. after taking the medication.

[0180] (5) Statistical methods

[0181] Data were analyzed using SPSS 23.0 software. Measurement data from different groups were described using mean ± standard deviation (x±s) and analyzed using t-tests. Ridit analysis was used to compare ordinal data. A p-value < 0.05 was considered statistically significant.

[0182] (6) Research Results

[0183] 1) General Information

[0184] Patient compliance was good in this clinical study, with no adverse reactions observed during treatment. A total of 60 patients were enrolled, excluding dropouts. All selected patients were female. The mean age in the observation group was 40.36±5.12 years, with a disease duration of 0.4–5.3 years, and a mean of 2.88±2.11 years. The mean age in the control group was 41.37±6.11 years, with a disease duration of 0.5–6.2 years, and a mean of 3.02±2.32 years. There were no statistically significant differences in baseline characteristics between the two groups (P>0.05), indicating comparability.

[0185] 2) Clinical efficacy comparison for treating breast hyperplasia: The total effective rate in the treatment group was 90%, while the total effective rate in the control group was 33.67%. The difference between the two groups was statistically significant (P<0.05). The treatment results are shown in Table 13.

[0186] Table 13 Comparison of treatment efficacy before and after treatment in the two groups (n=30)

[0187]

[0188] *P<0.05 (Comparison before and after treatment)

[0189] 3) Thyroid function

[0190] The results showed that the thyroid function of patients in both the observation group and the control group was within the normal range before and after treatment. The T3, T4, FT3, and FT4 levels before and after treatment were normally distributed according to the normality test. The paired T-test showed no statistically significant difference between the pre- and post-treatment data (P > 0.05), indicating that the thyroid function of the patients selected in this clinical observation did not change after JBKL treatment. The data are detailed in Table 14.

[0191] Table 14 Effects of different treatment groups on thyroid function (n=30, mean±SD)

[0192]

[0193] 4) Effects on thyroid antibodies

[0194] After treatment, the levels of anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) in the observation group significantly decreased. Before treatment, TGAb and TPOAb were 855.22±125.50 IU / mL and 550.67±130.45 IU / mL, respectively; after 12 weeks of treatment, they decreased to 430.85±52.45 IU / mL and 280.12±60.34 IU / mL, respectively. A paired t-test was performed to compare the levels before and after treatment. Both TGAb and TPOAb levels showed a statistically significant decrease (P<0.01), and the decrease was also statistically significant compared with the control group (P<0.01). After 24 weeks of treatment, TGAb and TPOAb levels decreased to 125.45±22.18 and 92.67±18.20, respectively. Paired t-tests confirmed statistically significant decreases before and after treatment (P<0.01), and the decreases in both TGAb and TPOAb were statistically significant compared with the control group (P<0.01). This suggests that this combination significantly reduces the levels of thyroid autoantibodies in patients with TGAb and TPOAb. Detailed data are shown in Table 15.

[0195] Table 15 Effects of different treatment groups on thyroid autoantibodies (n=30, mean±SD)

[0196]

[0197] Note: This indicates a statistically significant difference compared to before treatment, as determined by a paired t-test (P<0.01). # This indicates that, compared with the control group after treatment, there was a statistically significant difference (P<0.01) according to the paired t-test.

[0198] 5) Comparison of breast lumps: Before treatment, there were no significant differences in breast pain scores, lump size scores, and lump texture scores between the observation group and the control group, making them comparable. After treatment, the breast pain scores, lump size scores, and lump texture scores in both groups decreased significantly compared to before treatment, with statistically significant differences (P < 0.01). Furthermore, between the groups, the breast pain scores, breast lump size scores, and lump texture scores in the treatment group were significantly lower than those in the control group (P < 0.01). See Table 16.

[0199] Table 16 Comparison of breast pain and lumps before and after treatment (n=30, mean±SD)

[0200]

[0201] Note: * This indicates that, compared with before treatment, there was a highly statistically significant difference within the group (P<0.05) according to the paired t-test. ** This indicates that, compared with before treatment, there was a highly statistically significant difference within the group (P<0.01) according to the paired t-test. ## This indicates that, compared with the control group after treatment, there was a statistically significant difference (P<0.01) according to the paired t-test.

[0202] 6) Safety indicators: During the 6 months before and after treatment, routine blood, urine, and stool tests, as well as liver and kidney function tests, were all within the normal range for both groups of patients. No other adverse reactions occurred in either group of patients during the medication period.

[0203] Therefore, it is evident that the traditional Chinese medicine composition of the present invention has a clear therapeutic effect on Hashimoto's thyroiditis complicated with breast hyperplasia. The traditional Chinese medicine composition of the present invention achieves this effect through a multi-target regulatory mechanism:

[0204] ①Thyroid-breast cross-system synergistic treatment (simultaneously reducing thyroid antibodies and improving symptoms of breast hyperplasia);

[0205] ② Overall relief of symptoms related to qi stagnation, phlegm and blood stasis (pain, nodules, emotional abnormalities);

[0206] ③ It maintains endocrine homeostasis (no fluctuation in thyroid function), filling the clinical gap of lacking traditional Chinese medicine compound preparations for Hashimoto's thyroiditis complicated with breast hyperplasia.

[0207] Example 7: Hashimoto's thyroiditis complicated with thyroid nodules and breast hyperplasia

[0208] Patient Information: Female, 35 years old, presented with a 3-month history of neck swelling and breast tenderness. Past Medical History: Long-term high work stress, occasional anxiety, no family history of thyroid cancer. Diagnostic Criteria: Thyroid examination, ultrasound: diffuse thickening of the thyroid gland, with a 0.54cm × 0.38cm hypoechoic nodule (TI-RADS 3) in the right lobe, showing abundant blood flow signals. Thyroid Function: TSH normal, FT4 normal, TPOAb 653 IU / mL (↑), TgAb 487 IU / mL (↑). Diagnosis: Hashimoto's thyroiditis (HT) with benign thyroid nodules. Breast Examination: Ultrasound: bilateral breast glandular thickening, pain score 15.23, mass size score 3.82, mass texture score 6.28, no malignant signs. Diagnosis: fibrocystic breast disease. Traditional Chinese Medicine Diagnosis: Qi stagnation and phlegm-stasis type. Comprehensive diagnosis: Qi stagnation and phlegm stasis type, Hashimoto's thyroiditis (HT) with benign thyroid nodules and breast hyperplasia.

[0209] Treatment plan: A traditional Chinese medicine compound formula was used, consisting of ginseng 3g, astragalus 9g, fritillaria 30g (15g each of Sichuan fritillaria and Zhejiang fritillaria), prunella vulgaris 15g, smilax china 15g, turmeric 10g, and scutellaria baicalensis 12g. The decoction was prepared, divided into two equal portions, and taken twice daily, morning and evening, for 6 consecutive months. Thyroid function and ultrasound were re-examined to observe changes in thyroid nodules and breast hyperplasia. Lifestyle recommendations included a low-fat diet (to reduce estrogen stimulation), regular sleep patterns, chest expansion exercises, and hot compresses and massage (10 minutes daily). Psychological counseling included mindfulness-based stress reduction to improve anxiety (emotional stress can exacerbate endocrine disorders). Follow-up results: After 3 months: TPOAb 321 IU / mL (↑), TgAb 232 IU / mL (↑); thyroid nodules did not enlarge, and breast tenderness was significantly reduced. Six months later: TPOAb and TgAb were normal; the thyroid nodule shrank to 0.34cm×0.22cm; breast pain disappeared; the lump size score was 1.23; the lump texture score was 2.12; and the breast lump was significantly smaller.

[0210] Therefore, it can be seen that the traditional Chinese medicine composition of the present invention has multiple effects such as clearing heat and detoxifying, promoting blood circulation and removing blood stasis, and tonifying qi and strengthening the spleen. It can dissipate thyroid nodules, reduce breast hyperplasia, and improve the symptoms of Hashimoto's thyroiditis. This shows that the traditional Chinese medicine composition of the present invention has a good therapeutic effect on Hashimoto's thyroiditis complicated with thyroid nodules and breast hyperplasia.

[0211] The preferred embodiments of the present invention have been described in detail above. It should be understood that those skilled in the art can make numerous modifications and variations based on the concept of the present invention without creative effort. Therefore, all technical solutions that can be obtained by those skilled in the art based on the concept of the present invention through logical analysis, reasoning, or limited experimentation on the basis of existing technology should be within the scope of protection defined by the claims.

Claims

1. A traditional Chinese medicine composition for the prevention and treatment of Hashimoto's thyroiditis and its complications, characterized in that, It is made from the following raw materials in parts by weight: ginseng 1-5 parts, astragalus 7-11 parts, fritillaria 27-33 parts, prunella vulgaris 12-18 parts, smilax china 12-18 parts, turmeric 8-12 parts, scutellaria baicalensis 9-15 parts; the fritillaria cirrhosa is composed of fritillaria cirrhosa from Sichuan and fritillaria thunbergii in a weight ratio of 1:1, the turmeric is turmeric from Guangxi, and the complications are thyroid nodules and / or breast hyperplasia.

2. The traditional Chinese medicine composition as described in claim 1, characterized in that, It is made from the following raw materials in parts by weight: ginseng 3 parts, astragalus 9 parts, fritillaria 30 parts, prunella vulgaris 15 parts, smilax china 15 parts, turmeric 10 parts, and scutellaria baicalensis 12 parts.

3. The method for preparing the traditional Chinese medicine composition according to any one of claims 1-2, characterized in that, Includes the following steps: S1: Weigh the raw materials according to the formula. First decoction: Add 9-11 times the amount of water to the herbs, soak for 1.5 hours, reflux and extract for 1-2 hours, and filter. Second decoction: Add 9-11 times the amount of water to the dregs, reflux and extract for 1-2 hours, and filter. Combine the two filtrates to obtain the extract. S2: The extract is concentrated under reduced pressure at 60-80℃ and a vacuum of 0.02-0.08 MPa to a relative density of 1.02-1.05 to obtain the concentrated extract; S3: Spray dry the concentrated extract with an inlet air temperature of 160-200℃, an injection speed of 20-30 rpm, and a preheating temperature of 80-95℃ to obtain the dry extract powder. S4: Mix the dry powder with excipients, dry granulate and sizing to produce a medicine.

4. The method for preparing the traditional Chinese medicine composition as described in claim 3, characterized in that, The excipient mentioned in S4 is maltodextrin, and the granulation is carried out using a 10-mesh sieve and a 40-mesh sieve.

5. The use of the traditional Chinese medicine composition according to any one of claims 1-2 in the preparation of a medicament for treating Hashimoto's thyroiditis.

6. The use of the traditional Chinese medicine composition according to any one of claims 1-2 in the preparation of a medicament for treating Hashimoto's thyroiditis complicated with thyroid nodules and / or breast hyperplasia.

7. The application as described in any one of claims 5-6, characterized in that, The drug is in the form of granules, tablets, capsules, or oral liquid.

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