Traditional Chinese medicine composition for preventing and treating hashimoto's thyroiditis and complications thereof as well as preparation method and application of traditional Chinese medicine composition

Abstract

The invention discloses a traditional Chinese medicine composition for preventing and treating hashimoto's thyroiditis and complications thereof (thyroid nodules and / or hyperplasia of mammary glands). The traditional Chinese medicine composition is prepared from the following raw material medicines in parts by weight: 1-10 parts of ginseng, 1-15 parts of astragalus membranaceus, 1-40 parts of fritillaria, 1-20 parts of selfheal, 1-20 parts of chinaroot greenbrier, 1-18 parts of curcuma aromatica and 1-19 parts of scutellaria baicalensis. In addition, the invention further discloses a preparation method and application of the traditional Chinese medicine composition. Clinical efficacy and pharmacological studies prove that the traditional Chinese medicine composition has multiple effects of clearing away heat and toxic materials, promoting blood circulation to remove blood stasis, tonifying qi and spleen and the like, and the purposes of eliminating thyroid nodules, relieving hyperplasia of mammary glands and improving the symptom of hashimoto's thyroiditis are achieved.

Description

Technical Field

[0001] The present invention relates to a traditional Chinese medicine composition, in particular to a traditional Chinese medicine composition for preventing and treating Hashimoto's thyroiditis and its complications (thyroid nodules and / or breast hyperplasia). In addition, the present invention also relates to a preparation method and application of the traditional Chinese medicine composition. Background Art

[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 common, with approximately 20%-30% of patients with Hashimoto's thyroiditis having thyroid nodules. This is particularly true in women, where the incidence of both thyroid nodules and breast hyperplasia is higher. HT is more common in women aged 30-50 years. The incidence of thyroid nodules increases with age, becoming particularly common in those over 40 years old. The incidence in women is significantly higher 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 a significant role in the development of Hashimoto's thyroiditis, with a strong familial clustering. Breast hyperplasia is also more common in women of childbearing age (25-45 years), with a peak incidence in the 35-40 age group. The two conditions overlap significantly 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 the general population (risk is 2-3 times higher). The prevalence of breast hyperplasia in the general female population is 70%-80%, but Hashimoto's patients may have an increased risk due to endocrine-immune disorders.

[0003] HT is an autoimmune disease. Generally, patients produce anti-thyroid peroxidase antibodies (TPOAb) and anti-thyroglobulin antibodies (TgAb), which lead to chronic inflammation and destruction of thyroid tissue. When a large number of lymphocytes infiltrate the thyroid tissue, it will eventually lead to hypothyroidism. If the thyroid tissue of patients with Hashimoto's thyroiditis is attacked by the immune system for a long time, it may cause hyperplasia or degeneration of thyroid follicular epithelial cells, and then form nodules. The nature of nodules is diverse, including hyperplastic nodules, colloid nodules, cystic nodules, etc., and a few may be malignant nodules (thyroid cancer). Hashimoto's thyroiditis may be asymptomatic in the early stages and manifest as hypothyroidism in the later stages (such as fatigue, chills, weight gain, dry skin, etc.). Even if thyroid nodules are present, most of them are asymptomatic nodules. Some patients may feel a lump in the neck, and a few patients may experience symptoms such as difficulty swallowing and hoarseness due to compression of the nodules. Western medicine has no effective treatment for HT combined with nodules. Early intervention for HT is generally not performed. If thyroid dysfunction occurs, levothyroxine sodium (L-T4) is generally used. L-T4 is the preferred medication for Hashimoto's thyroiditis combined with hypothyroidism. It can improve thyroid function and may even reduce nodules in some patients. For patients with larger nodules, significant compression symptoms, or suspected malignancy, partial or complete thyroidectomy may be performed. Other treatments, such as selenium preparations and vitamin D, can modulate immune function and have a certain auxiliary effect on lowering antibody levels. Scientists have discovered a certain connection between the breast and the thyroid gland. Both are regulated by the "hypothalamic-pituitary-glandular axis" and influenced by estrogen levels. Many studies have shown that the correlation between thyroid and breast diseases mainly stems from hormonal interactions (such as the thyroid hormone → prolactin / estrogen axis) and a shared immune-inflammatory background. Therefore, thyroid dysfunction in Hashimoto's patients (such as hypothyroidism or hyperthyroidism) can affect the metabolism of hormones such as estrogen and prolactin. Hashimoto's patients also have chronic immune abnormalities and elevated levels of proinflammatory factors (such as IL-6 and TNF-α) in the body, which may indirectly affect the breast tissue microenvironment through systemic inflammation.

[0004] Traditional Chinese Medicine considers thyroid nodules combined with thyroid hyperplasia (HT) to be a type of goiter, with the etiology often linked to emotional trauma, dietary imbalances, and inappropriate diet and soil. The pathogenesis primarily involves liver depression and qi stagnation, phlegm coagulation and blood stasis, and spleen and kidney yang deficiency, leading to the accumulation of qi, phlegm, and blood stasis in the neck, resulting in goiter. Breast hyperplasia is closely related to the liver and spleen, primarily due to liver depression and spleen deficiency, and the accumulation of phlegm and blood stasis. Both are emotionally driven. Therefore, the concept of "different diseases treated with the same treatment" is applied to the treatment of Hashimoto's thyroiditis combined with breast hyperplasia.

[0005] Currently, there are numerous patents for traditional Chinese medicines (TCMs) for Hashimoto's thyroiditis combined with thyroid nodules, primarily focusing on TCM compositions with immunomodulatory, anti-inflammatory, and anti-edema properties, as well as nodule-softening and nodule-dispersing effects. This study improves upon a previous patent application (patent application number: 202010950834.4). The TCM composition comprises Fritillaria cirrhosa, Smilax china, Ginseng, and Prunella vulgaris. During the application process for the previous patent application (patent application number: 202010950834.4), the following deficiencies were identified: ① While effective only for Hashimoto's thyroiditis, the TCM composition is only moderately effective for combined thyroid nodules. ② In cases of Hashimoto's thyroiditis combined with thyroid nodules, female patients often also suffer from breast hyperplasia. This TCM composition does not alleviate the symptoms of breast hyperplasia, and no TCM composition currently exists that can simultaneously treat both Hashimoto's thyroiditis combined with thyroid nodules and breast hyperplasia. ③ The TCM composition's ability to suppress thyroid immune damage still requires further improvement. Therefore, this patent has improved and optimized the previous patent, greatly enhancing the breadth of indications and therapeutic effects. Summary of the Invention

[0006] In order to overcome at least one of the deficiencies in the above-mentioned prior art, the present invention provides a traditional Chinese medicine composition for preventing and treating Hashimoto's thyroiditis and its complications, as well as a preparation method and application thereof.

[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 prepared from the following raw materials in parts by weight: 1-10 parts of ginseng, 1-15 parts of astragalus, 1-40 parts of fritillaria, 1-20 parts of selfheal, 1-20 parts of smilax china, 1-18 parts of turmeric, and 1-19 parts of scutellaria.

[0008] The preferred ratio of the above raw materials is: 1-5 parts of ginseng, 7-11 parts of astragalus, 27-33 parts of fritillaria, 12-18 parts of selfheal, 12-18 parts of smilax, 8-12 parts of turmeric, and 9-15 parts of scutellaria.

[0009] The preferred ratio of the above raw materials is: 3-5 parts of ginseng, 9-11 parts of astragalus, 30-33 parts of fritillaria, 15-18 parts of selfheal, 15-18 parts of smilax, 10-12 parts of turmeric, and 12-15 parts of scutellaria.

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

[0011] In other embodiments, the Fritillaria is composed of Fritillaria cirrhosa and Fritillaria thunbergii in a weight ratio of 1:1, the Curcuma is Curcuma aromatica, and the above-mentioned complications are thyroid nodules and / or breast hyperplasia.

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

[0013] S1: Weigh the raw materials according to the ratio, decoct for the first time: add 9-11 times the amount of water to the medicinal materials, soak for 1.5 hours, reflux and extract at a low boiling temperature for 1-2 hours, and filter; decoct for the second time: add 9-11 times the amount of water to the medicinal residue, reflux and extract at a low boiling temperature 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°C and a vacuum degree of 0.02-0.08 MPa to a relative density of 1.02-1.05 (measured at 60±2°C) to obtain a concentrated clear paste;

[0015] S3: spray drying the concentrated paste, with an air inlet temperature of 160-200°C, an injection speed of 20-30 rpm, and a preheating temperature of the liquid of 80-95°C to obtain a dry paste powder;

[0016] S4: Mix the dry paste powder with auxiliary materials, dry granulate and granulate to prepare medicine.

[0017] In other embodiments, the auxiliary material in S4 is maltodextrin, and the whole granules are screened using a 10-mesh sieve and a 40-mesh sieve.

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

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

[0020] In other embodiments, the above-mentioned medicine is in the form of granules, tablets, capsules or oral solutions.

[0021] The Chinese medicine used in the present invention has accurate efficacy, safety, reliability and significant efficacy. Among them, Fritillaria is a general term for a class of perennial herbs, belonging to the genus Fritillaria of the Liliaceae family (Liliaceae). Its dried bulb is the core part of traditional Chinese medicinal materials, including Fritillaria cirrhosa, Fritillaria thunbergii and Fritillaria truncatula. Fritillaria cirrhosa moisturizes dryness, Fritillaria thunbergii disperses stagnation, and Fritillaria truncatula reduces phlegm. Fritillaria cirrhosa and Fritillaria truncatula are preferably used in the present invention; Ginseng is the dried root and rhizome of Panax ginseng (Araliaceae family), which has four core effects: invigorating vital energy, tonifying spleen and lung, promoting fluid and tranquilizing the mind, improving intelligence and resisting aging; Astragalus is the dried root of Astragalus membranaceus or Astragalus mongolica of the genus Astragalus of the Leguminosae family, which has the clinical commonly used tonic effect of invigorating qi and raising yang, consolidating exterior and stopping sweating, promoting diuresis and reducing swelling, supporting toxins and promoting tissue regeneration; Prunella vulgaris is Prunella vulgaris (Lamiaceae family) vulgaris, harvested in summer when the fruit clusters are reddish-brown, has the core efficacy of clearing liver fire and relieving depression; Smilax china is the dried rhizome of Smilax china, a plant of the Liliaceae family, characterized by tubercle-like protrusions and reddish-brown ring marks on the cross section, and has the core efficacy of dispelling wind and dampness, detoxifying and relieving blood stasis; Scutellaria baicalensis is the dried root of Scutellaria baicalensis, a plant of the Lamiaceae family, and has the core efficacy of clearing heat and dampness, purging fire and detoxifying; Curcuma zedoaria is Curcuma wenyujin, Curcuma longa, Curcuma kwangsiensis or Curcuma truncatum, a plant of the Zingiberaceae family. The dried tubers of turmeric (Curcuma phaeocaulis) are harvested in winter after the stems and leaves wither, freed of sediment and fine roots, steamed or boiled until thoroughly cooked, and then dried. They have the core benefits of promoting blood circulation and relieving pain, promoting qi and relieving depression, clearing the heart and cooling blood, and promoting bile and jaundice. Among these, the tubers of turmeric, Curcuma australis, contain significantly higher levels of curcumin than other varieties, which is the material basis for its anti-inflammatory and hepatoprotective activities. Curcuma australis is preferred for use in this invention.

[0022] The theory of Traditional Chinese Medicine is to soothe the liver and regulate qi, resolve phlegm and dissipate stagnation, activate blood circulation and remove blood stasis, and warm and nourish the spleen and kidneys. According to Traditional Chinese Medicine theory, the above-mentioned Chinese herbal medicine composition is mainly composed of Prunella Vulgaris and Fritillaria cirrhosa to clear heat and resolve phlegm, disperse stagnation and reduce swelling, supplemented by ginseng and astragalus to replenish qi and strengthen the body's resistance, while Smilax china and Curcuma aromatica to promote blood circulation and remove blood stasis, soothe the liver and relieve depression, and Scutellaria baicalensis to clear heat, detoxify and reduce swelling. Together, they act on Hashimoto's thyroiditis combined with thyroid nodules and breast hyperplasia, treating both local lesions and regulating systemic qi and blood, achieving the effect of treating both the symptoms and the root cause. This prescription embodies the principle of TCM syndrome differentiation and treatment, and comprehensively regulates the key pathogenesis of Hashimoto's thyroiditis - qi and yin deficiency and the intertwining of phlegm and blood stasis. The overall idea of ​​this prescription is to achieve the purpose of dissipating thyroid nodules, alleviating breast hyperplasia, and improving the symptoms of Hashimoto's thyroiditis through multiple effects such as clearing heat and detoxifying, activating blood circulation and removing blood stasis, and replenishing qi and strengthening the spleen.

[0023] The beneficial effects of the present invention are: through the above-mentioned traditional Chinese medicine composition, the inhibition of thyroid immune damage is further improved, and it has a good therapeutic effect on Hashimoto's thyroiditis combined with thyroid nodules, and has a clear and good therapeutic effect on Hashimoto's thyroiditis combined with breast hyperplasia. At the same time, it also has a clear and good therapeutic effect on Hashimoto's thyroiditis combined with thyroid nodules and breast hyperplasia.

[0024] The concept, specific implementation methods and technical effects of the present invention will be further described below to fully understand the purpose, characteristics and effects of the present invention. DETAILED DESCRIPTION

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

[0026] Example 1 Prescription Screening and Optimization

[0027] In the early stages, we used a traditional Chinese medicine composition consisting of 15 grams of Fritillaria cirrhosa, 15 grams of Smilax china, 9 grams of Panax ginseng, and 15 grams of Prunella vulgaris to treat Hashimoto's thyroiditis. This prescription is also effective in treating thyroid nodules. However, in order to screen the most ideal drug for treating Hashimoto's thyroiditis combined with thyroid nodules, we selected the human thyroid follicular epithelial cell line Nthy-ori 3-1 and THP-1 cell line to conduct a prescription screening study. The thyroid immune damage inhibition experiment based on the THP-1 / Nthy-ori 3-1 co-culture model was specifically carried out as follows:

[0028] 1. 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 were co-cultured with Nthy-ori 3-1 thyroid cells 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: Add the drug to be tested (various medicinal materials and compound prescriptions) at a final concentration of 5 μg / mL to the model group

[0036] 3. Drug pretreatment:

[0037] (1) All drugs to be tested must undergo cytotoxicity testing in advance and their EC50 values ​​must be screened;

[0038] (2) The final concentration of 5 μg / mL was uniformly used for activity screening, and the drug intervention was 12 hours. Six replicate wells were set up in each group.

[0039] 4. Testing indicators:

[0040] (1) Cell supernatant was collected and the levels of thyroid peroxidase antibody (TPOAb), interleukin-6 (IL-6) and thyroxine (T4) were detected.

[0041] 2. Experimental results are shown in Table 1

[0042] 1. Model Validation

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

[0044] 2. Effects of single medicinal materials:

[0045] Compared with the model group, each single herb group (astragalus, turmeric, fritillaria cirrhosa, smilax china, ginseng, prunella vulgaris, and scutellaria baicalensis) significantly reduced TPOAb and IL-6 levels (P<0.05 or P<0.01); among them, astragalus and turmeric had the most significant effect on increasing T4 levels (P<0.01).

[0046] 3. Effects of compound combination:

[0047] (1) Four-ingredient compound prescription (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 extremely significantly increased (P<0.01).

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

[0049] 3. Conclusion

[0050] A seven-ingredient compound consisting of ginseng, astragalus, Fritillaria cirrhosa, Prunella vulgaris, Smilax china, Curcuma aromatica, 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 Chinese herbal medicine combinations on thyroid antibodies, inflammation, and function (n=6)

[0052]

[0053] Note: Compared with the normal group, a means P < 0.01, b means P < 0.05

[0054] The above experiment verified the significant synergistic effect of the seven-ingredient compound in regulating thyroid function indicators (T4), autoimmune indicators (TPOAb) and inflammatory factors (IL-6) through standardized cell models and unified drug concentration (5μg / mL). Its effect is better than that of single medicinal materials and the combination of four-ingredient compound. It can be seen that the 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 medicinal materials and the four-ingredient compound combination (Fritillaria cirrhosa, Smilax china, Ginseng and Prunella vulgaris).

[0055] Example 2 Orthogonal experiment for prescription optimization

[0056] To address the balance between affordability and efficacy of key medicinal ingredients in the compound, this example aims to clarify the following questions through orthogonal experimental design: The Qi-tonifying herbs ginseng and astragalus have different prices, raising the question of whether they can be substituted; the dosage and price differences between Fritillaria cirrhosa and Fritillaria thunbergii are also significant, raising the question of whether their efficacy differs; and Curcuma aromatica and Scutellaria baicalensis have significant effects on improving thyroid function and nodules, necessitating further investigation of their dosages. While maintaining the same dosages of 15g for Prunella vulgaris and 15g for Smilax china, we propose a three-factor, three-level orthogonal experiment to further optimize the formula. 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 4), including 9 experimental groups, each of which represents a combination of factors and levels, namely A1B1C1, A1B2C2, A1B3C3, A2B1C2, A2B2C3, A2B3C1, A3B1C3, A3B2C1, A3B3C2 and other 9 combinations. Purchase 10 times the amount of each of the 9 prescriptions, and prepare them into dry extracts by conventional water pre-boiling method. The co-culture method of thyroid cells and immune cells was used to screen the best prescription by comparing antibody indicators, thyroid function indicators and inflammation level differences, namely 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 that characterize thyroid function as the main effect indicators to screen the prescriptions. The smaller the TPOAb and IL-6 values, the better. The overall evaluation normalization method was used to evaluate the OD value "normalization value. The smaller the value, the better the indicator d i =(y max -y i ) / (y max -y min ), the two factors use weighted value OD = 0.6y1 i +0.4y2 i By calculating the mean level 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 interaction combinations were: A2×B2 was 0.976, A3×C3 was 0.872, and B2×C3 was 0.845. The A2B2C3 combination showed a significant synergistic effect (theoretical value 0.976 > the independent sum of each factor 0.590+0.636+0.713=1.939 / 3=0.646). Analysis of variance showed that factor A had a highly significant effect on OD values ​​(F=28.44, P<0.001), and the A×B interaction was significant (P=0.038), suggesting a synergistic effect between Fritillaria and Curcuma + Scutellaria. The best parameter combination is A2B2C3, that is, the compound composed of 15g of Fritillaria cirrhosa, 15g of Fritillaria thunbergii, 15g of Prunella vulgaris, 10g of Curcuma aromatica, 5g of Smilax china, 12g of Scutellaria baicalensis, 3g of Ginseng, and 9g of Astragalus membranaceus has the best effect.

[0060] Table 3-1 Three-factor three-level screening results

[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: All data are the average of 6 replicate wells. max =120.12, TPOAb min =90.78;IL-6 max =337.40,IL-6 min =224.92

[0063] Table 3-2 Factor level average and range value table

[0064]

[0065]

[0066] Example 3 Preparation of Composition Extract and Granules

[0067] Raw material ratio: take 3kg of ginseng, 9kg of astragalus, 30kg of Fritillaria (15kg of Sichuan Fritillaria, 15kg of Zhejiang Fritillaria), 15kg of Prunella Vulgaris, 15kg of Smilax china, 10kg of Curcuma aromatica, and 12kg of Scutellaria baicalensis, a total of 94kg of Chinese herbal medicine slices.

[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, gently boil under reflux for 1.5 hours, and filter; Second decoction: Add 10 times the amount of water (940L) to the medicinal residue, gently boil under reflux 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°C and a vacuum degree of 0.02-0.08 MPa; the relative density is concentrated to 1.02-1.05 (60±2°C) to obtain a concentrated clear paste (dry paste rate 16%-22%);

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

[0072] S4: Granulation: Mix the dry paste powder with an appropriate amount of maltodextrin; shape the mixture using a dry granulator, and sieve through a 10-mesh sieve and a 40-mesh sieve to obtain granules (codenamed JBKL), which are packaged into 12g / bags.

[0073] Example 4 Effect on Nodular Goiter Model Rats

[0074] SD male rats weighing 120-140g were selected. All rats were raised in an SFP-level laboratory and kept in an environment with a temperature of 25±2°C and a humidity of 60±5%. The lighting system usually adopted a 12-hour light / 12-hour dark cycle to maintain the physiological rhythm of the animals. Standard feed and drinking water were provided daily, and the sterilized bedding was changed once a week. The rats began to be modeled after 2 weeks of adaptation to the environment. Among them, the normal group (n=10) was gavaged with physiological saline at 1ml / 100g body weight daily, while the remaining mice were gavaged with 0.1% propylthiouracil (PTU) solution at 1ml / 100g body weight, once a day in the morning for 8 weeks. After the model preparation was completed, color Doppler ultrasound was used to determine whether the model of each group was successful, and 50 rats with successful models were selected. The model animals were randomly divided into groups after being numbered, with 10 animals in each group, namely the model control group (Model group), the high-dose dry paste powder group of the combination (JB-H group, the dose was 14.44 g / kg (equivalent to the original medicinal material)), the medium-dose dry paste powder group of the combination (JB-M group, the dose was 7.22 g / kg (equivalent to the original medicinal material)), the low-dose dry paste powder group of the combination (JB-L group, the dose was 3.61 g / kg (equivalent to the original medicinal material)), and the levothyroxine sodium tablets group (L-T4 group).

[0075] Drug administration began at the 9th week. The L-T4 group was gavaged with 0.1mg / L L-T4 solution at 1ml / 100g body weight; the drug administration groups were given the above doses to JB-H, JB-M and JB-L respectively; the Model group and the normal group were gavaged with distilled water at 1ml / 100g body weight. All groups were gavaged once a day at 8:00 am for 8 consecutive weeks. After the end of the drug administration, the rats were anesthetized by intraperitoneal injection of 2% sodium pentobarbital (3mL / kg). After successful anesthesia, blood was collected from the abdominal aorta. The skin of the neck was then cut open to expose the trachea, and the thyroid tissue on both sides was found and completely separated, and other tissues such as muscle were removed. A portion of the right thyroid gland of each rat was cut and placed in a 1.5ml EP tube and stored in a -20℃ refrigerator for later use. SPSS 27.0 statistical software was used for statistical analysis. The measurement data were expressed as "mean ± standard deviation" (x ± s). One-way analysis of variance was used for comparison among multiple groups, and the LSD method was used for pairwise comparison. P < 0.05 was considered statistically significant.

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

[0077] Compared with the normal group, the thyroid mass and relative weight of the rats in the Model group were 158.37 ± 27.23 mg, with a relative mass increase of 0.375 ± 0.071‰ (P < 0.01); compared with the Model group, the thyroid mass of the L-T4 group was 98.45 ± 14.37 mg, with a relative mass decrease of 0.228 ± 0.015‰ (P < 0.01). Compared with the Model group, the thyroid mass of the JB-H group was 101.37 ± 16.26 mg, with a relative mass decrease of 0.248 ± 0.024‰ (P < 0.01). Moreover, compared with the Model group, the thyroid mass of the JB-M group was 112.34 ± 20.19 mg, with a relative mass decrease of 0.273 ± 0.062‰ (P < 0.01). This shows that JB (i.e., the Chinese medicine composition of the present invention) can significantly reduce the mass 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 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: Compared with the normal group, the difference is statistically significant (P<0.01); ** Compared with the normal group, the difference is statistically significant; ## Compared with the model group, the difference was statistically significant (P<0.01).

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

[0082] The results of the serum thyroid function index study showed that compared with the normal group, the serum TSH level of rats in the Model group was significantly increased to 4.81±0.77μIU / L (P<0.05), and the FT3 and FT4 levels were significantly decreased to 5.29±0.39pmol / L (P<0.01) and 7.19±0.50pmol / L respectively. Compared with the Model group, the serum TSH level of rats in the L-T4 group, LH-H group, and LH-M group was significantly decreased (P<0.05 or P<0.01); the FT3 and FT4 levels were significantly increased, with statistical significance (P<0.01), indicating that JB (i.e., the traditional Chinese medicine composition of the present invention) can effectively improve the thyroid function of rats with nodular thyroid. 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) Effect of JB composition (i.e., dry powder obtained from S3 in Example 3) on thyroid

[0087] Ultrasound examination showed that the anterior-posterior, medial-lateral and lateral diameters of the thyroid gland in the model group were significantly larger than those in the normal group. The glands in the model group were also asymmetrically enlarged, with nodules in the lateral lobes without capsules, with fuzzy and irregular boundaries, and scattered strong echoes of punctate or strip-like fibrous hyperplasia. In addition, compared with the normal group, the volume of the left and right thyroid glands in the model group was also significantly increased (P<0.01), increasing to 35.1±2.67mm, respectively. 3 and 32.11±2.65mm 3 . The bilateral goiters in the L-T4 group decreased significantly, which was statistically significant (P<0.01). Moreover, the volumes of the left and right thyroid glands in the JB-H, JB-M and JB-L groups decreased significantly, which was statistically significant (P<0.05 or P<0.01). In addition, ultrasound examination showed that some small nodules in the JB-H and JB-M groups were significantly reduced. The above results show that JB (i.e., the Chinese medicine composition of the present invention) can significantly improve goiter and significantly reduce small nodules in some 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 means P < 0.01, b means P < 0.05

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

[0092] Thyroid tissue pathology observation Pathological examination showed that HE staining of thyroid sections of rats in the model group showed that the follicles of the thyroid tissue of rats in the normal group were arranged regularly and uniformly, mostly spherical or oval, and there was no interstitial inflammatory cell infiltration. However, the shape and follicle size of the thyroid tissue in the model group were irregular, with large differences, and the epithelial cells were significantly proliferative, arranged in disorder, and the colloid was compressed and unevenly distributed. The thyroid tissue follicles of rats in the L-T4 group, JB-H group, and JB-M group had reduced swelling, a small amount of peripheral hyperplasia, reduced internal papillary structures, and regular epithelial cell arrangement. The swelling of thyroid epithelial cells and interstitial inflammatory cell infiltration in rats in the JB-H group were significantly improved.

[0093] According to the above experimental data, the Chinese medicine composition of the present invention has the following comprehensive therapeutic effects on rats with nodular goiter induced by propylthiouracil:

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

[0095] Thyroid function recovery: 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), while FT4 increased to 9.85±0.85 pmol / L (P<0.01).

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

[0097] Histopathological repair: The model group showed uneven thyroid follicle 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. The JB-H group showed the most significant pathological repair effect.

[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 structural disorder and inflammatory infiltration, which comprehensively demonstrates that it has a clear therapeutic effect on Hashimoto's thyroiditis combined with thyroid nodules.

[0099] Example 5 Clinical Observation of Hashimoto's Thyroiditis Combined with Thyroid Nodules

[0100] To determine the clinical efficacy of the Chinese medicine composition of the present invention, a single-center, randomized, double-blind, controlled clinical trial was conducted. Eighty patients diagnosed with Hashimoto's thyroiditis and thyroid nodules, whose TCM syndromes were classified as Qi deficiency and phlegm stasis, were selected for observation. The patients were randomly divided into a control group and an observation group of 40 patients each, with a treatment course of 24 weeks.

[0101] (1) Western medicine diagnostic criteria, based on the Internal Medicine Journal and the 2008 Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China, are mainly characterized by positive serum thyroid peroxidase antibodies (TPOAb) and / or thyroglobulin antibodies (TGAb) in thyroid autoantibody testing. Thyroid ultrasound examinations show diffuse heterogeneous changes in the thyroid gland, or thickening of the isthmus, varying degrees of heterogeneous echogenic areas, and thyroid nodules, and ultrasound findings do not support malignant nodules.

[0102] (2) Diagnostic criteria for TCM syndromes: Refer to the Internal Medicine of Traditional Chinese Medicine, the Guidelines for Clinical Research of New Chinese Medicine Drugs, and the Surgery of Traditional Chinese Medicine for goiter and qi deficiency and phlegm stasis: ① Main symptoms: a lump in the front of the neck with a firm texture, a smooth surface and a nodular feel, which can move up and down with swallowing, and the nodule does not disappear for a long time, with no symptoms or accompanied by neck discomfort. ② Secondary symptoms: fatigue, shortness of breath and laziness to speak, anxiety, chest tightness and discomfort, poor appetite, constipation or loose stools, etc. Tongue: pale or red tongue with a thin coating (thin white or thin yellow) or no coating. Pulse: deep and stringy pulse or deep and astringent pulse. Patients who meet all the main symptoms and one or more of the secondary symptoms can be diagnosed by referring to the tongue and pulse.

[0103] (4) Inclusion criteria for case selection: ① Patients who meet the diagnostic criteria for Hashimoto's thyroiditis with nodules; ② Patients with Qi deficiency and phlegm stasis type according to TCM syndrome differentiation, and gender is female; ③ Ultrasound detection of thyroid nodules showing solid, cystic or calcified nature; ④ TSH, FT3, and FT4 values ​​within the normal range; ⑤ Patients aged between 18 and 60 years; ⑥ Patients who are willing to accept observation and have the conditions to persist in completing the process.

[0104] (5) Exclusion criteria: 1) Patients with hypothyroidism or subclinical hypothyroidism; 2) Patients with thyroid nodules and ultrasound examination showed C-TIRADS 4A or above nodules; 3) Patients with other thyroid diseases, such as primary hyperthyroidism, Graves' disease, thyrotoxicosis, subacute thyroiditis, thyroid lymphoma or thyroid malignant tumor; 4) Patients who have received immunotherapy, selenium preparations, Chinese medicine intervention or other drugs that affect the efficacy evaluation for any reason in the past month, or those who have participated in any clinical trial (enrolled and used study drugs) within 3 months before screening; 5) Previous history of thyroid radioactive iodine treatment or surgery; 6) Patients with other malignant tumors; 7) Patients with severe heart disease. , brain, liver, kidney, digestive tract, blood system and other diseases; ALT, AST>1.5 times the upper limit of normal reference value; blood creatinine>upper limit of normal reference value; 8) People with mental or nervous system diseases who cannot take medicine on time or abuse drugs and other substances; 9) People with other serious autoimmune diseases and have received immunomodulatory treatment within 3 months, including but not limited to type 1 diabetes, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, inflammatory bowel disease, autoimmune adrenocortical insufficiency, systemic lupus erythematosus, etc.; 10) Pregnant or lactating women, and those planning to become pregnant in the near future; 11) People who are known or suspected to be allergic to the trial drug; 12) People who are considered unsuitable for clinical trials for other reasons by researchers.

[0105] (6) Prohibited medication: During the entire trial period, in addition to the study drugs, the following Chinese and Western medicines and related therapies that may affect the efficacy of the drugs are prohibited: ① Selenium preparations, glucocorticoids, statins and other Western medicines that interfere with the efficacy of the disease; ② Traditional Chinese medicine compounds and their preparations for improving thyroid inflammation and function, such as Chaihu Shugan San plus or minus, Xiaoyao San plus or minus, Zhizi Qinggan Tang plus or minus, Haizao Yuhu plus or minus, etc., shall not be used during the trial; ③ Thyroid hormone replacement medication.

[0106] (7) Exit (dropout) criteria: ① occurrence of serious adverse events; ② poor compliance of the subject; ③ the subject is pregnant or preparing to become pregnant; ④ the subject participates in any other clinical trial of clinical drugs during the study, or participates in any medical research that conflicts scientifically or medically with this study;

[0107] (8) Treatment methods and dosing cycles

[0108] Observation group: The granules prepared in part of Example 3 (JBKL) were taken orally, 1 bag at a time, twice a day, for 24 consecutive weeks.

[0109] Control group: "JB Simulator Granules" (containing 1% JB extract) (JB-SIM) were taken orally, 1 bag at a time, twice a day, for 24 consecutive weeks.

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

[0111] (9) Observation indicators

[0112] 1) Main efficacy indicators

[0113] After 24 weeks of treatment, the proportion of subjects whose anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) titers decreased by 50% was evaluated. Thyroid nodule diameter was assessed using thyroid color Doppler ultrasound. If multiple nodules were present, the largest diameter of the largest nodule was used as the data. Thyroid nodule diameters were recorded before and after treatment.

[0114] 2) Secondary efficacy indicators

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

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

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

[0118] (10) Statistical methods

[0119] All data were analyzed and processed using professional statistical software. Measurement data were presented as mean ± standard deviation. If normal distribution and homogeneous variance were observed, paired sample t-tests were used to compare pre- and post-treatment parameters to determine the significance of the difference in efficacy. Enumeration data were presented as percentages of cases, and the chi-square test was used for statistical analysis between the two groups. If data did not conform to a normal distribution, the results were presented as median (Q1, Q3) interquartile ranges, and the Wilcoxon rank sum test was used. A P value greater than 0.05 indicated no statistically significant difference, and a P value less than 0.05 indicated a statistically significant difference.

[0120] (11) Research conclusion

[0121] 1) General Information

[0122] This clinical study demonstrated good patient compliance, with no adverse reactions reported during treatment. A total of 80 patients were enrolled, with no dropouts. All patients were female, with a mean age of 43.78±8.26 years in the observation group and 42.16±8.26 years in the control group. There was no significant difference in age between the two groups (P>0.05), indicating that the two groups were comparable in age.

[0123] 2) Thyroid function

[0124] The results of the study showed that the thyroid function of the patients in the observation group and the control group were within the normal range before and after treatment. The thyroid function triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), and free thyroxine (FT4) before and after treatment were in line with the normal distribution after normality test. The paired T test method was used for the data before and after treatment, and it was found that there was no statistically significant difference between the data before and after treatment (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 shown in Table 7 for details.

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

[0126]

[0127]

[0128] 3) Effect on thyroid antibodies

[0129] After JBKL treatment, the anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) in the observation group decreased significantly. Before treatment, TGAb and TPOAb were 729.11±118.12IU / mL and 436.34±122.12IU / mL, respectively. After 12 weeks of treatment, they decreased to 321.12±50.12IU / mL and 267.76±64.56IU / mL, respectively. Paired t-test showed that there was no significant difference between the two groups before and after treatment. The decrease 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 decreased to 120.11±20.11IU / mL and 89.13±17.94IU / mL, respectively. Paired t-test showed that there was a significant decrease before and after treatment (P<0.01), and compared with the observation group, the decrease in TGAb and TPOAb was statistically significant (P<0.01). This suggests that the Chinese medicine composition of this patent has a significant effect on reducing the level 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: Indicates that the observation group showed significant statistical difference compared with the group before treatment (P<0.01) by paired t-test. ## Compared with the control group after treatment, there was a significant statistical difference (P<0.01) through paired t test.

[0133] 4) Impact on thyroid nodules

[0134] After JBKL treatment, the diameter of the patient's thyroid nodules in the observation group was reduced. Before treatment, the diameter of the thyroid nodules was 12.11 ± 3.56 mm. After 12 weeks of treatment, the diameter of the nodules decreased to 8.53 ± 2.11 mm. Using the paired T test method, it was shown that the difference between the treatment and the pre-treatment was statistically significant (P < 0.01); after 24 weeks of treatment, the diameter of the nodules decreased to 6.33 ± 1.38 mm. Using the paired T test method, it was shown that the difference between the treatment and the pre-treatment was statistically significant (P < 0.01). After treatment in the control group, there was no significant change in the diameter of the thyroid nodules. This shows that after 24 weeks of treatment with the Chinese medicine composition of the present invention, the diameter of the patient's 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: Indicates that the observation group showed significant statistical difference compared with the group before treatment (P<0.01) by paired t-test. ## Indicates that there was a significant statistical difference between the observation group and the control group after treatment (P<0.01) through paired t test.

[0138] In addition, data on the diameter of thyroid nodules before and after treatment were analyzed. Based on the criteria for evaluating the efficacy of thyroid nodule treatment, the following criteria were used: ① Markedly effective: Thyroid ultrasound examination showed that the diameter of the thyroid nodule after treatment was 1 / 2 or more smaller than before treatment. ② Effective: Thyroid ultrasound examination showed that the diameter of the thyroid nodule after treatment was reduced by 1 / 3, but less than 1 / 2. ③ Ineffective: Thyroid ultrasound examination showed that the diameter of the thyroid nodule after treatment was reduced by less than 1 / 3, or even increased in size. Note: Calculation formula: (Nodule diameter before treatment - Nodule diameter after treatment) / Nodule diameter before treatment × 100%. The total effective rate after 24 weeks of JBKL treatment was 67.5%, while the total effective rate in the control group was 7.5%. Detailed data are shown in Table 10.

[0139] Table 10 Effectiveness of different treatment groups for thyroid nodules

[0140]

[0141]

[0142] 5) Impact on TCM syndromes

[0143] The total score of TCM syndromes was significantly improved. At baseline, the total score of TCM syndromes was 14.57±6.37. After 12 weeks of JBKL treatment, the total score of TCM syndromes was 9.68±4.35. The paired t-test before and after treatment was statistically significant (P<0.01), and the difference was also statistically significant compared with the control group (P<0.01). After 24 weeks of treatment, the total score of TCM syndromes was 4.68±3.12. The paired t-test before and after treatment was statistically significant (P<0.01), and the difference was also statistically significant compared with the control group (P<0.01). The results of the study showed that the Chinese medicine composition of the present 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: Compared with before treatment, there is a significant statistical difference (P<0.01) by paired t test; ## Compared with the control group after treatment, there was a significant statistical difference (P<0.01) through paired t test.

[0147] It can be seen that the Chinese medicine composition of the present invention does have a clear therapeutic effect on Hashimoto's thyroiditis combined with thyroid nodules. The Chinese medicine composition of the present invention has the following effects through a multi-target regulation mechanism:

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

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

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

[0151] Example 6 Clinical Observation of the Present Invention on Hashimoto's Thyroiditis Combined with Breast Hyperplasia

[0152] To determine the clinical efficacy of the Chinese herbal composition of the present invention for Hashimoto's thyroiditis combined with breast hyperplasia, a single-center, randomized, double-blind, controlled clinical trial was conducted. Sixty patients diagnosed with Hashimoto's thyroiditis and thyroid nodules, whose TCM syndromes were classified as Qi stagnation and phlegm stasis, were selected for observation. The patients were randomly divided into a control group and an observation group of 30 patients each, with a treatment course of 24 weeks.

[0153] (1) Western medicine diagnostic standards

[0154] Diagnosis of Hashimoto's thyroiditis: It is formulated with reference to the "Internal Medicine" and the 2008 "Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China". The main manifestation is that the thyroid autoantibody test can show positive serum thyroid peroxidase antibodies (TPOAb) and / or thyroglobulin antibodies (TGAb).

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

[0156] 1) Clinical symptoms: Periodic pain (swelling, stabbing, or dull pain) in one or both breasts, which may radiate to the chest, flanks, shoulders, and back. The pain intensity is correlated with the menstrual cycle or mood swings, and the course of the disease is ≥ 3 months (continuous or intermittent cumulative).

[0157] 2) Physical characteristics: Single / multiple nodules are palpable, with diverse shapes and unclear boundaries, no adhesion to the skin and deep tissues, good mobility, and the size may increase or decrease with the menstrual cycle or mood changes.

[0158] 3) Exclusion criteria: Premature breast development (before Tanner stage II), gynecomastia, and benign or malignant breast tumors (need to be confirmed by pathology).

[0159] 4) Imaging evidence: verified by breast ultrasound (BI-RADS classification ≤ 3) or mammography (ACR appropriateness criteria) to exclude malignant signs.

[0160] (2) The TCM syndrome differentiation criteria (Qi stagnation and phlegm stasis syndrome) are implemented in accordance with the "Guiding Principles for Clinical Research of New Chinese Medicines (Trial Implementation)": (1) Main symptoms: breast pain with periodic nodular changes, tightness in the neck, phlegm stagnation in the throat, and depression. (2) Secondary symptoms: flank pain (migratory), poor appetite, sighing, and significant mood swings. (3) Tongue and pulse characteristics: red / light red tongue, thin yellow or slightly greasy fur, and stringy / slippery pulse. Diagnosis requires: ≥3 main symptoms; ≥2 secondary symptoms; combined with characteristic tongue and pulse manifestations.

[0161] (3) Subject inclusion criteria

[0162] 1) Core inclusion criteria: Patients met the diagnostic criteria of the Journal of Internal Medicine and the 2008 Guidelines for the Diagnosis and Treatment of Thyroid Diseases in China. Patients were also diagnosed in accordance with the Expert Consensus on the Diagnosis and Treatment of Cystic Hyperplasia (2016) and the Traditional Chinese Medicine (TCM) criteria for Qi stagnation and Phlegm Stasis (referring to the ICD-11 Traditional Medicine Module); had a disease duration of ≥3 months and were in the active phase (VAS pain score ≥4); and were women of childbearing age (20-50 years old) who were not pregnant or breastfeeding.

[0163] 2) Compliance requirements: Voluntary signing of the informed consent form and commitment to complete all follow-up nodes; complete baseline data (including imaging, laboratory and traditional Chinese medicine four diagnosis records).

[0164] 3) Subject exclusion criteria

[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 calcification, abnormal blood supply); severe heart, liver, or kidney dysfunction (Child-Pugh C or eGFR < 30 mL / min) or endocrine metabolic diseases such as diabetes and pituitary tumors.

[0166] Physiological status exclusions: positive pregnancy test or breastfeeding women; known allergy history or allergic constitution (involving study drug components).

[0167] Interference factors excluded from the study included: receiving hormone replacement therapy or immunomodulators in the past 3 months; having mental disorders (DSM-V diagnostic criteria) or cognitive dysfunction (MMSE < 24 points), which would affect study compliance.

[0168] (4) Treatment methods

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

[0170] Control group: "JB Simulator Granules" (containing 1% JB extract) (JB-SIM) were taken orally, 1 bag at a time, twice a day, for 24 consecutive weeks.

[0171] The basic treatment for the two groups is the same, including psychological counseling, mood regulation, avoidance of spicy and irritating foods, proper exercise, and avoidance of fatigue.

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

[0173] (5) Observation indicators and methods

[0174] 1) Evaluation of efficacy

[0175] Clinical efficacy was determined according to the Guiding Principles for Clinical Research of New Traditional Chinese Medicines. ① Markedly effective: Clinical symptoms significantly improved or essentially disappeared, or improved by more than 30% compared to pre-treatment levels. ② Effective: Clinical symptoms improved somewhat, or improved by 10% to 29% compared to pre-treatment levels. ③ Ineffective: Clinical symptoms showed no significant improvement, or the condition progressed or even worsened.

[0176] 2) Main Outcome Measures: ① Thyroid antibodies (TPOAb, TgAb) and thyroid function (TT3, TT4, FT3, FT4, TSH) were measured in both groups before and after treatment. ② Breast elasticity ultrasound examinations were performed 7 days after the end of menstruation before and after treatment to assess breast pain and lumps (breast lump size was measured by the maximum diameter). The efficacy evaluation criteria for fibrocystic breast disease are shown in Table 12.

[0177] Table 12 Evaluation criteria for the efficacy 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 medicine.

[0180] (5) Statistical methods

[0181] Data were analyzed using SPSS 23.0 software. Measurement data between groups were described using x-values ​​(χ2) and t-tests, and rank data were compared using Ridit analysis. P < 0.05 was considered statistically significant.

[0182] (6) Research results

[0183] 1) General Information

[0184] This clinical study showed good patient compliance, with no adverse reactions reported during treatment. A total of 60 patients were enrolled, excluding dropouts. All patients were female. The mean age of the observation group was 40.36±5.12 years, with a disease course of 0.4 to 5.3 years (average 2.88±2.11 years); the mean age of the control group was 41.37±6.11 years, with a disease course of 0.5 to 6.2 years (average 3.02±2.32 years). There was no statistically significant difference in baseline data between the two groups (P>0.05), indicating comparability.

[0185] 2) Comparison of Clinical Efficacy on Hyperplasia of Mammary Gland The total effective rate of the treatment group was 90%, while that of 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 therapeutic effects between the two groups before and after treatment (n=30)

[0187]

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

[0189] 3) Thyroid function

[0190] The results of the study showed that the thyroid function of the patients in the observation group and the control group was within the normal range before and after treatment. The T3, T4, FT3, and FT4 before and after treatment were in line with the normal distribution after normality test. The paired T test method was used for the data before and after treatment, and it was found that there was no statistically significant difference between the data before and after treatment (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 shown in Table 14 for details.

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

[0192]

[0193] 4) Effect on thyroid antibodies

[0194] After treatment, the anti-thyroid peroxidase antibody (TPOAb) and anti-thyroglobulin antibody (TgAb) in the observation group decreased significantly. Before treatment, TGAb and TPOAb were 855.22±125.50IU / mL and 550.67±130.45IU / mL, respectively. After 12 weeks of treatment, they decreased to 430.85±52.45IU / mL and 280.12±60.34IU / mL, respectively. Paired t-test showed that the levels of TGAb and TPOAb in the observation group decreased significantly before and after treatment. Both 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 decreased to 125.45±22.18 and 92.67±18.20, respectively. Paired t-tests showed a statistically significant decrease before and after treatment (P<0.01), and compared with the control group, the decreases in TGAb and TPOAb were statistically significant (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: Compared with before treatment, there is a significant statistical difference (P<0.01) by paired t test; # Compared with the control group after treatment, there was a significant statistical difference (P<0.01) through paired t test.

[0198] 5) Comparison of Breast Lumps: Before treatment, there were no significant differences in breast pain scores, lump size scores, or lump texture scores between the observation and control groups, indicating comparability. After treatment, breast pain scores, lump size scores, and lump texture scores in both groups decreased significantly compared to pre-treatment scores (P < 0.01). Furthermore, intergroup comparisons showed that breast pain scores, 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 mass before and after treatment (n=30, mean±SD)

[0200]

[0201] Note: * Indicates that there is a very significant statistical difference (P<0.05) between the group and before treatment by paired t test; ** Indicates that there is a very significant statistical difference (P<0.01) between the group and before treatment by paired t test; ## Compared with the control group after treatment, there was a significant statistical difference (P<0.01) through paired t test.

[0202] 6) Safety Indicators: During the six months before and after treatment, the blood, urine, and stool routine tests, as well as liver and kidney function, were all within normal ranges in both groups. No other adverse reactions were reported during the medication period.

[0203] It can be seen that the Chinese medicine composition of the present invention does have a clear therapeutic effect on Hashimoto's thyroiditis combined with breast hyperplasia. The Chinese medicine composition of the present invention achieves the following through a multi-target regulation mechanism:

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

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

[0206] ③ Maintain endocrine homeostasis (no fluctuation in thyroid function), filling the clinical gap of the lack of Chinese herbal compound preparations for Hashimoto's thyroiditis combined with breast hyperplasia.

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

[0208] Patient information: Female, 35 years old, came to the hospital for "neck swelling and breast tenderness for 3 months". Past medical history: long-term work pressure, occasional emotional anxiety, no family history of thyroid cancer. Diagnostic basis: thyroid examination, ultrasound: diffuse echo thickening of the thyroid gland, 0.54cm×0.38cm low-echo nodule in the right lobe (TI-RADS 3 category), rich blood flow signal. Thyroid function: normal TSH, normal FT4, TPOAb 653IU / mL (↑), TgAb 487IU / 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: Cystoma. 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 formula was used: 3g of ginseng, 9g of astragalus, 30g of Fritillaria (15g each of Sichuan Fritillaria and Zhejiang Fritillaria), 15g of Prunella Vulgaris, 15g of Smilax china, 10g of Curcuma aromatica, and 12g of Scutellaria baicalensis. The decoction was divided into two equal portions and taken once in the morning and evening for 6 months. Thyroid function tests and ultrasounds were then performed to observe changes in thyroid nodules and breast hyperplasia. Lifestyle recommendations included a low-fat diet (to reduce estrogen stimulation), a regular sleep and rest schedule, chest expansion exercises, and hot compress massage (10 minutes daily). Psychological counseling using mindfulness-based stress reduction was used to improve anxiety (emotional stress can exacerbate endocrine disorders). Follow-up results: After 3 months, TPOAb levels increased to 321 IU / mL (↑), TgAb levels increased to 232 IU / mL (↑); the thyroid nodules did not enlarge, and breast tenderness and pain were significantly reduced. After 6 months: TPOAb was normal, TgAb was 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 reduced.

[0210] It can be seen from this that the traditional Chinese medicine composition of the present invention has multiple effects such as clearing away heat and detoxifying, promoting blood circulation and removing blood stasis, replenishing qi and strengthening the spleen, etc., which can dissipate thyroid nodules, alleviate breast hyperplasia, and improve the symptoms of Hashimoto's thyroiditis, indicating that the traditional Chinese medicine composition of the present invention does have a good therapeutic effect on Hashimoto's thyroiditis combined 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 numerous modifications and variations based on the concepts of the present invention can be made by one of ordinary skill in the art without inventive effort. Therefore, any technical solution that can be derived by one of ordinary skill in the art through logical analysis, reasoning, or limited experimentation based on the concepts of the present invention and the prior art should be within the scope of protection defined by the claims.

Claims

1. A Chinese medicine composition for preventing and treating Hashimoto's thyroiditis and its complications, characterized in that: The invention is prepared from the following raw materials in parts by weight: 1-10 parts of ginseng, 1-15 parts of astragalus, 1-40 parts of fritillaria, 1-20 parts of selfheal, 1-20 parts of smilax china, 1-18 parts of turmeric and 1-19 parts of scutellaria.

2. The Chinese medicine composition according to claim 1, wherein The invention is prepared from the following raw materials in parts by weight: 1-5 parts of ginseng, 7-11 parts of astragalus, 27-33 parts of fritillaria, 12-18 parts of selfheal, 12-18 parts of smilax, 8-12 parts of turmeric and 9-15 parts of scutellaria.

3. The Chinese medicine composition according to claim 1, wherein The medicinal preparation is prepared from the following raw materials in parts by weight: 3 parts of ginseng, 9 parts of astragalus, 30 parts of fritillaria, 15 parts of selfheal, 15 parts of smilax, 10 parts of turmeric and 12 parts of scutellaria.

4. The Chinese medicine composition according to any one of claims 1 to 3, wherein The fritillaria is composed of cirrhosa fritillaria and thunbergia fritillaria in a weight ratio of 1:1, the turmeric is radix curcumae, and the complication is thyroid nodules and / or breast hyperplasia.

5. The method for preparing the Chinese medicine composition according to any one of claims 1 to 4, wherein: The steps include: S1: Weigh the raw materials according to the ratio, decoct for the first time: add 9-11 times the amount of water to the medicinal materials, soak for 1.5 hours, reflux and extract at a low boiling temperature for 1-2 hours, and filter; decoct for the second time: add 9-11 times the amount of water to the medicinal residue, reflux and extract at a low boiling temperature 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° C. and a vacuum degree of 0.02-0.08 MPa to a relative density of 1.02-1.05 to obtain a concentrated clear paste; S3: spray drying the concentrated paste, with an air inlet temperature of 160-200°C, an injection speed of 20-30 rpm, and a preheating temperature of the liquid of 80-95°C to obtain a dry paste powder; S4: Mix the dry paste powder with auxiliary materials, dry granulate and granulate to prepare medicine.

6. The method for preparing the Chinese medicine composition according to claim 5, wherein: The auxiliary material in S4 is maltodextrin, and the whole granulation is performed using a 10-mesh sieve and a 40-mesh sieve.

7. Use of the traditional Chinese medicine composition according to any one of claims 1 to 4 in preparing a medicament for treating Hashimoto's thyroiditis.

8. Use of the Chinese medicine composition according to any one of claims 1 to 4 in the preparation of a medicament for treating Hashimoto's thyroiditis combined with thyroid nodules and / or breast hyperplasia.

9. The use according to any one of claims 7 to 8, characterized in that The medicine is in the form of granules, tablets, capsules or oral liquids.

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