Preparation method of granules for treating breast nodules, thyroid nodules and canceration

Abstract

The invention discloses a preparation method of granules for treating breast and thyroid nodules and canceration, which comprises the following steps: S1, raw material preparation: preparing 199g of codonopsis pilosula, 332g of astragalus membranaceus, 149g of glossy privet fruit, 100g of herba epimedii, 166g of selfheal, 100g of uniflower swisscentaury root, 100g of rhizoma pinellinae praeparata, 100g of curcuma zedoary, 199g of salvia chinensis, 332g of selaginella doederleinii hieron, 100g of curcuma aromatica and 149g of cortex albiziae according to a mass ratio; s2, adding water to decoct the twelve medicines twice, adding 8 times by mass of water for the first time, extracting for 2.0 hours, and filtering; s3, adding 6 times by mass of water for the second time, extracting for 1.5 hours, filtering, and combining filtrates; s4, concentrating under reduced pressure to obtain clear paste with the relative density of about 1.05-1.10 (60 DEG C); and S5, performing vacuum drying, crushing into fine powder, adding dextrin and 10g of stevioside, uniformly mixing, granulating with 75% by volume of ethanol, drying, preparing into 1000g, and packaging, thereby obtaining the product.

Description

Technical Field

[0001] The invention belongs to the technical field of traditional Chinese medicine preparations, and particularly relates to a method for preparing particles for treating breast and thyroid nodules and canceration. Background Art

[0002] Breast and thyroid nodules and tumors (such as breast cancer and thyroid cancer) often cause lumps in the breast or neck, seriously affecting patients' quality of life and health. Currently, treatments for these lumps primarily include surgical resection, radiotherapy, chemotherapy, and targeted therapy, but these methods are often associated with significant trauma, side effects, and recurrence. Furthermore, while traditional Chinese medicine or topical therapies have some efficacy, they have limitations such as slow onset, poor drug penetration, and unclear targets.

[0003] In recent years, granular formulations have garnered widespread attention in the field of tumor treatment due to their portability, stability, and high bioavailability. However, existing granular formulations for treating breast and thyroid tumors still suffer from complex preparation processes, imprecise release of active ingredients, and inconsistent efficacy. Therefore, there is an urgent need to develop granular formulations with a simple preparation process, strong targeting, and proven efficacy to address these shortcomings and provide a safer and more effective treatment option for clinical practice. Summary of the Invention

[0004] To address the lack of effective, convenient, and minimally side-effecting granules for treating breast and thyroid nodules and cancer, the present invention provides a method for preparing granules for treating breast and thyroid nodules and cancer. These granules can be used to treat breast or neck lumps caused by breast cancer, thyroid cancer, or thyroid nodules, accompanied by fatigue, chest tightness, anxiety or depression, and restlessness and insomnia. Based on traditional Chinese medicine theory and modern pharmaceutical preparation techniques, the present invention optimizes the formulation and process, aiming to provide a method for preparing granules that can significantly reduce tumors, alleviate symptoms, and have minimal side effects, demonstrating significant clinical application value.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A method for preparing particles for treating breast and thyroid nodules and cancerous changes, comprising the following steps:

[0007] S1. Raw material preparation: according to the mass ratio, prepare 199g of Codonopsis pilosula, 332g of Astragalus membranaceus, 149g of Ligustrum lucidum fruit, 100g of Epimedium, 166g of Prunella vulgaris, 100g of Rhizoma Cyperi, 100g of Pinellia ternata, 100g of Curcuma zedoaria, 199g of Lithospermum officinale, 332g of Cyperus rotundus, 100g of Curcuma aromatica, and 149g of Albizia julibrissin bark;

[0008] S2. Decoction the above twelve ingredients twice with water, adding 8 times the weight of water for the first decoction, extract for 2.0 hours, and filter.

[0009] S3, add 6 times the mass of water for the second time, extract for 1.5 hours, filter, and combine the filtrate;

[0010] S4, concentrating under reduced pressure to a clear paste with a relative density of about 1.05 to 1.10 (60°C);

[0011] S5. Vacuum drying, crushing into fine powder, adding dextrin and 10 g of steviol glycoside, mixing, granulating with 75% volume fraction ethanol, drying, making into 1000 g, and packaging.

[0012] Furthermore, the packaging described in S5 is 8g / bag.

[0013] The preparation method of the Fuzheng Tiaoqi Jiedu granules of the present invention, the main chemical components and physicochemical properties of each medicinal ingredient in the prescription are as follows:

[0014] 1. Chemical composition of Codonopsis pilosula:

[0015] It mainly includes flavonoids, alkaloids, phenylpropanoids, steroids, polysaccharides and other ingredients, such as alfalfa, apigenin, luteolin-7-O-β-D-glucoside, belamcandide, luteolin-5-O-β-D-glucoside, alfalfa, luteolin 7-rutinoside, kaempferol, luteolin 7-galactoside, luteolin, luteolin glycoside, emodin, kaempferol, quercetin, codonopsis pilosula, codonopsis pilosula alkaloid, ligustol, tryptophan, choline chloride, niacin, codonopsis pilosula C, codonoside, stigmasterol, α-spinasterol, stigmaster-7-en-3-one, stigmaster-7-en-3-ol, β-carotene, D-fructose, D-glucose, sucrose, kestose, kestose, shikimic acid, maleic acid, oleanolic acid, suberenone, etc.

[0016] 2. Chemical components of Astragalus:

[0017] It mainly includes polysaccharides, saponin compounds, flavonoids, amino acids, trace elements and other ingredients, such as astragalus polysaccharide, acetyl astragalus saponin, hydroxy isoflavones, formononetin, calycosin isoflavones, quercetin, rutin, glycyrrhizin, luteolin, daidzein, genistein, asparagine, aspartic acid, threonine, proline, lysine, arginine, valine, Sc, Se, Cr, Cu, Zn, Mn, Co, Si, Mo, Ca, P , Cs, La, Ce, Fe, K, Rb, Sm, sucrose, mucilage, bitter substances, amylase, coumarin, vitamin D, riboflavin, vanillic acid, isoferulic acid, ferulic acid, chlorogenic acid, linolenic acid, caffeic acid, niacin, coumarin, niacin, starch E, carotene, betaine, niacinamide, linoleic acid, folic acid, lupeol, β-sitosterol, palmitic acid, rosmarinic acid, protocatechuic acid, 4-hydroxybenzoic acid, hyperoside, hesperidin, etc.

[0018] 3. Chemical composition of Ligustrum lucidum:

[0019] It mainly includes triterpenes, flavonoids, volatile oils, iridoids, polysaccharides, phenylethanoid glycosides, fatty acids, amino acids and trace elements, such as oleanolic acid, methyl oleanolic acid, lupeol, ursolic acid, acetyloleanolic acid, apigenin, luteolin, quercetin, quercetin-3-O-rutinoside, cosmos glycoside, wild sumac glycoside, eriodictyol, kaempferol, kaempferol-3-O-glucoside, kaempferol-3-O-rutinoside, salidroside, verbascoside, echinacea glycoside, beishengmaning, privet glycoside, dimethyl oleate, oleuropein, neoprivet glycoside, sucrose, rhamnose, arabinose, glucose, fucose, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, hemolytic phosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine and phosphatidic acid.

[0020] 4. Chemical components of Epimedium:

[0021] It mainly includes flavonoids, lignans, polysaccharides, alkaloids and other ingredients, such as epimedium A, epimedium B, epimedium C, icariin, fructose, mannose, ribose, rhamnose, glucose, galactose, xylose, arabinose, fucose, cedarwood A, (+)-cyclooleuropein, (+)-candelilla resin phenol, (+)-cyclooleuropein, cedarwood C, Ca, K, Mg, Fe, Zn, etc. It also contains trace amounts of sterols, chromones, tannins, sesquiterpenes, phenanthrene, anthraquinone and other ingredients.

[0022] 5. Chemical composition of Prunella vulgaris:

[0023] Mainly including terpenes, phenolic acids, flavonoids, organic acids, volatile oils and other ingredients, such as rutin, quercetin, rosmarinic acid, isorosmarinic acid glycosides, linoleic acid, squalene, β-amyrin, luteolin, kaempferol, sitosterol, caffeic acid, ursolic acid, protocatechuic aldehyde, salicylic acid, sinapic acid, syringic acid, p-coumaric acid, m-hydroxybenzoic acid, umbelliferone, scopoletin, esculin, chrysophanol, 2-hydroxy-3-methylanthraquinone, palmitic acid, squalene, linoleic acid, linolenic acid, stearic acid, oleic acid, glucose, galactose, xylose, arabinose, rhamnose, mannose, 3,4,α-trihydroxy Phenylpropanoid butyl ester, 3,4,α-trihydroxyphenylpropanoid methyl ester, methylrosmarinin, E-butylrosmarinin, Z-butylrosmarinin, methylrosmarinate, trans-isorosmarinic acid glucoside, trans-rosmarinic acid glucoside methyl ester, 3,4-dihydroxyphenylpropionic acid, α-bosterol, β-sitosterol, α-spinasterone, vitamin C, carotene, 1,8-cineole, β-pinene acid, myrcene, linalyl acetate, α-phellandrene, linalool, 1,6-cyclodecanediol, hexadecanoic acid, hexatriacontane, 9-octadecene, tetradecane, dodecanal, n-heneicosane, etc.

[0024] 6. Chemical composition of loofah:

[0025] It mainly includes lignans, phenylpropanoids, flavonoids, terpenes and sterones, such as 20-hydroxyecdysterone, roentgenasterone, scutellaria sterone C, 25S-cypridosterone, amaranthosterone A, turketosterone, 22-keto-20-hydroxyecdysterone, 11α-hydroxypoststerone, 20-hydroxyecdysterone-3-ethyl acetate, (+)-1-hydroxypinoresinol 1-β-D-glucose, isovitex irone, (24R)-11α,20,24-trihydroxyecdysterone, podocarposterone C, rudosterone R1, rudosterone, β-sitosterol, 4'-demethyl rudosterone aglycone, 4'-demethyl rudosterone, kaempferol-3,7-dioxo-α-L-dirhamnoside, arctiol-A, coniferin, arctidic acid, luteolin, apigenin, catechin, summer cyanidin, oleanolic acid, humulic acid, ursolic acid, stigmasterol, etc.

[0026] 7. Chemical components of French Pinellia:

[0027] It mainly includes alkaloids, flavonoids, organic acids, volatile oils and other ingredients, such as inosine, guanosine, adenosine, succinic acid, β-sitosterol, aspartic acid, threonine, serine, glutamic acid, glycine, alanine, arginine, lysine, palmitic acid, stearic acid, oleic acid, α-linolenic acid, β-linolenic acid, L-ephedrine hydrochloride, anethole, hexadecenedioic acid, butyl vinyl ether, 3-acetamido-5-methylisoxazole, dauctoside, brassicasterol, 3-hydroxy-5,22-diene-stigmasterol, 3-hydroxy-5,24-diene-stigmasterol, cycloaltinol, dauctoside palmitate, glycyrrhizin, ammonium glycyrrhizate, etc.

[0028] 8. Chemical components of Curcuma zedoaria:

[0029] It mainly includes two major components: volatile oil and curcumin, such as curcumol, curcumone, curcumadione, germacone, β-elemene, (4S)-4-hydroxycinnamalactone, curcumenol, curcumene, β-sitosterol, lupeol, glyceryl laurate, monoglyceride of tridecanoate, dibutyl phthalate, etc.

[0030] 9. Chemical composition of Iwami-no-Iwatani:

[0031] It mainly includes polysaccharides, terpenes, sterols, polyphenols and other ingredients, such as danshensu, protocatechuic acid, protocatechuic aldehyde, danshensu glucose, chlorogenic acid, coumaric acid, rosmarinic acid, salvianolic acid A, salvianolic acid J, salvianolic acid B, salvianolic acid C, rosmarinic acid methyl ester, caffeic acid glucose, ferulic acid, kaempferol, quercetin-3-O-glucoside, rutin, kaempferol-3-O-glucuronide and kaempferol-3-O-glucoside, 7-hydroxycoumarin, madecassic acid, ursolic acid, oleanolic acid, α-boswellic acid, β-sitosterol, sinaponic aldehyde, coniferyl aldehyde, syringaldehyde, 3-indolecarboxaldehyde, darutoside, hawthorn acid, ursolic acid, etc.

[0032] 10. Chemical composition of Cypress sphenanthera:

[0033] It mainly includes flavonoids, alkaloids, lignin, organic acids, sterols and other ingredients, such as p-hydroxybenzoic acid, m-hydroxybenzoic acid, 3-(3-hydroxy-phenyl)-propionic acid methyl ester, syringaresinol, cinnamic acid, catechol, 5,7-dihydroxychromone, p-hydroxybenzaldehyde, ferulic acid, syringaldehyde, p-methoxybenzoic acid, apigenin, palmitic acid, β-sitosterol, cypress biflavonoids, tachinella biflavonoids, ginkgo biflavonoids, shikimic acid, syringic acid, stearic acid, nobiletin, gallic acid, berberine, etc.

[0034] 11. Chemical components of Curcuma:

[0035] It mainly includes sesquiterpenes, monoterpenes, diterpenes, curcuminoids, polysaccharides, sterols, alkaloids, resins, polypeptides, flavonoids and other ingredients, such as pinene, β-pinene, camphor, isoborneol, α-terpineol, 5-allylguaiacol, 1-caryophyllene, curcumin, demethoxycurcumin, bisdemethoxycurcumin, tetramethylpyrazine, arabinose, fructose, glucose, ferulic acid, caffeic acid, coumaric acid, trans-cinnamic acid, croton epoxide, n-eicosanoic acid, germacone, curcumadione, dihydrocurcumadione, curcuma cyclodiene, curcumadione, curcumol, K, Na, Fe, Mg, Ca, etc.

[0036] 12. Chemical composition of Albizia Julibrissin bark:

[0037] It mainly includes triterpenes, lignans, flavonoids, sterols and other ingredients, such as acacic acid, cineole, ethyl dococarbonate, β-sitosterol, quercetin, carrot glycosides, 5,5'-dimethoxy-7-oxolariciressinol, (-)-eugenol, 1-(29-hydroxy-nonacosanolic acid)-glyceride, 1-(24-hydroxy-tetracosanolic acid)-glyceride, ethyl dococarbonate, 12-hydroxy-dodecanoic acid glyceride-1', acacic acid 3-O-β-D-pyranose Glucosyl (1→3)-β-D-pyranosyl (1→6) [β-D-pyranosyl (1→2)]-β-D-pyranosyl glucopyranoside, aurocin lactone 3-O-β-D-pyranosyl (1→2)-β-D-pyranosyl (1→6)-β-D-2-deoxy-2-acetylaminopyranosyl glucopyranoside, aurocin lactone 3-O-β-D-pyranosyl (1→2)-α-L-arabinopyranosyl (1→6)-β-D-2-deoxy-2-acetylaminopyranosyl glucopyranoside, etc.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. The preparation method of particles for treating breast and thyroid nodules and cancerous changes described in the present invention is derived from the clinical experience prescription summarized by the applicant in long-term clinical practice. The inventor studied the crushing process and molding process according to relevant requirements and obtained the method of the present application.

[0040] 2. The preparation method of the particles for treating breast and thyroid nodules and cancerous changes described in the present invention can be used to treat breast or neck lumps caused by breast cancer, thyroid cancer, and thyroid nodules, accompanied by fatigue, chest and flank tightness, anxiety or depression, restlessness and insomnia.

[0041] 3. The preparation method of the particles for treating breast and thyroid nodules and cancerous changes described in the present invention has the advantages of being easy to carry and store after the drug is prepared into particles, and having no restrictions on the time of use, and is inexpensive. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] The accompanying drawings are used to provide further understanding of the present invention and constitute a part of the specification. They are used to explain the present invention together with the embodiments of the present invention and do not constitute a limitation of the present invention.

[0043] Figure 1 This is a graph showing the effect of the granules for treating breast and thyroid nodules and cancer (Fuzheng Tiaoqi Jiedu Granules) on 4T1 cell viability;

[0044] Figure 2 This is a diagram showing the effect of the granules for treating breast and thyroid nodules and cancer (Fuzheng Tiaoqi Jiedu Granules) on 4T1 cell clone formation;

[0045] Figure 3 This is a graph showing the effect of the granules for treating breast and thyroid nodules and cancer (Fuzheng Tiaoqi Jiedu Granules) on the migration ability of 4T1 cells;

[0046] Figure 4 This is a graph showing the effect of the granules for treating breast and thyroid nodules and cancer (Fuzheng Tiaoqi Jiedu Granules) on the invasive ability of 4T1 cells;

[0047] Figure 5 This is a graph showing the effect of the granules for treating breast and thyroid nodules and cancer (Fuzheng Tiaoqi Jiedu Granules) on CXCR4 protein expression in 4T1 cells;

[0048] Figure 6 This is a flow chart of the preparation process of the particles for treating breast and thyroid nodules and cancerous changes according to the present invention;

[0049] Figure 7 This is a TLC identification chart of the Ligustrum lucidum fruit for treating breast and thyroid nodules and cancerous granules described in the present invention (1. Ligustrum lucidum fruit control medicinal material solution 15μl; 2. Fuzheng Tiaoqi Jiedu Granule 15μl; 3. Fuzheng Tiaoqi Jiedu Granule 15μl; 4. Fuzheng Tiaoqi Jiedu Granule 15μl);

[0050] Figure 8 This is the TLC identification chart of Prunella Vulgaris and Lithospermum officinale for treating breast, thyroid nodules and cancerous granules described in the present invention (1. Prunella Vulgaris control medicinal material solution 15μl; 2. Lithospermum officinale control medicinal material solution 15μl; 3. Fuzheng Tiaoqi Jiedu Granules 15μl; 4. Fuzheng Tiaoqi Jiedu Granules 15μl; 5. Fuzheng Tiaoqi Jiedu Granules 15μl). DETAILED DESCRIPTION

[0051] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. All other embodiments obtained by ordinary technicians in this field based on the embodiments of the present invention without making any creative efforts shall fall within the scope of protection of the present invention.

[0052] Example:

[0053] A method for preparing particles for treating breast and thyroid nodules and cancerous changes, such as Figure 6 As shown, the following steps are included:

[0054] S1. Raw material preparation: according to the mass ratio, prepare 199g of Codonopsis pilosula, 332g of Astragalus membranaceus, 149g of Ligustrum lucidum fruit, 100g of Epimedium, 166g of Prunella vulgaris, 100g of Rhizoma Cyperi, 100g of Pinellia ternata, 100g of Curcuma zedoaria, 199g of Lithospermum officinale, 332g of Cyperus rotundus, 100g of Curcuma aromatica, and 149g of Albizia julibrissin bark;

[0055] S2. Decoction the above twelve ingredients twice with water, adding 8 times the weight of water for the first decoction, extract for 2.0 hours, and filter.

[0056] S3, add 6 times the mass of water for the second time, extract for 1.5 hours, filter, and combine the filtrate;

[0057] S4, concentrating under reduced pressure to a clear paste with a relative density of about 1.05 to 1.10 (60°C);

[0058] S5. Vacuum drying, crushing into fine powder, adding dextrin and 10 g of steviol glycoside, mixing, granulating with 75% volume fraction ethanol, drying, making 1000 g, and packaging, that is, (8 g / bag).

[0059] Experimental example:

[0060] A granule for treating breast and thyroid nodules and cancer (hereinafter referred to as "Fuzheng Tiaoqi Jiedu Granule") prepared in the embodiment

[0061] 1. Research data and literature on the preparation process of Fuzheng Tiaoqi Jiedu Granules

[0062] 1.1 Prescription and preparation process design

[0063] [Prescription] See Example;

[0064] [Preparation method] See the embodiment;

[0065]

Detailed description of the preparation process route

[0066] Figure 6 The following is a flow chart of the preparation process of the particles for treating breast and thyroid nodules and cancerous changes; the process description is shown in Table 1.

[0067] Table 1 Description of the preparation process of a method for preparing particles for treating breast, thyroid nodules and cancer

[0068]

[0069]

[0070] 1.2. Preparation process research data

[0071] 1.2.1 Reasons for dosage form selection

[0072] Fuzheng Tiaoqi Jiedu Granules are a clinically proven formula that strengthens the body's qi, regulates qi, and resolves toxic substances. It is primarily indicated for breast or neck lumps caused by breast cancer, thyroid cancer, or thyroid nodules, along with fatigue, chest and flank tightness, anxiety or depression, restlessness, and insomnia. This product requires a large daily dosage of raw herbs, so it was formulated in granules. Granules retain the rapid action of traditional decoctions while overcoming their instability. Granules also offer excellent drug stability and are easy to produce, store, transport, carry, and use. Therefore, granules were chosen for this product.

[0073] 1.3 Research on water extraction process

[0074] 1.3.1. Examination of water absorption rate of medicinal slices

[0075] According to the prescription ratio, the following Chinese medicinal pieces were weighed: Codonopsis pilosula 12g, Astragalus 20g, Ligustrum lucidum 9g, Epimedium 6g, Prunella vulgaris 10g, Rhizoma Cyperi 6g, Pinellia 6g, Curcuma 6g, Lithospermum officinale 12g, Cyperus rotundus 20g, Curcuma aromatica 6g, and Albizia julibrissin bark 9g, totaling 122g. Three portions were prepared and soaked in 10 times the mass of water for 12h. The unabsorbed water was filtered out, the residue was weighed, and the absorption rate was calculated. The results are shown in Table 2.

[0076] Table 2 Water absorption test results

[0077]

[0078] The results showed that the water absorption of medicinal slices was about 1.15 times of their own weight.

[0079] 1.3.2. Examination of decoction frequency

[0080] Weigh the following Chinese herbal medicine slices according to the prescription ratio: 12g of Codonopsis pilosula, 20g of Astragalus membranaceus, 9g of Ligustrum lucidum fruit, 6g of Epimedium, 10g of Prunella vulgaris, 6g of Rhizoma Cyperi, 6g of Pinellia ternata, 6g of Curcuma zedoaria, 12g of Lithospermum officinale, 20g of Cyperus rotundus, 6g of Curcuma aromatica, and 9g of Albizia julibrissin bark, for a total of 122g. Decoction was performed three times with water: the first time, 8 times the weight of water was added and the decoction was performed for 2 hours; the second time, 6 times the weight of water was added and the decoction was performed for 1.5 hours; and the third time, 6 times the weight of water was added and the decoction was performed for 1.0 hour. Each extract was filtered and concentrated under reduced pressure. The volume of the extract was fixed to 1000ml. The yield of the dry paste from the first, second, and third decoctions was determined.

[0081] Determination of dry paste yield: Accurately pipette 25 ml of the extract of fixed volume, place it in an evaporating dish that has been dried to constant weight, evaporate to dryness in a water bath, dry at 105°C for 6 hours, take it out, cool it in a desiccator for 0.5 hours, weigh it quickly, and calculate the dry paste yield according to the following formula. The results are shown in Table 3.

[0082]

[0083] Note: W—dry paste weight (g); W1—total weight of slices (g); V—fixed volume (ml).

[0084] Table 3 Results of the examination on the number of decoctions

[0085]

[0086] The experimental results show that: taking the dry paste yield as the evaluation index, the dry paste yield of the third decoction accounts for 6.78% of the total dry paste yield of the three decoctions, indicating that the extraction is basically complete after two decoctions. Therefore, this product adopts the water extraction process of decoctioning twice.

[0087] 1.3.3 Examination of water addition

[0088] According to the prescription ratio, weigh the following Chinese herbal medicine slices: 12g of Codonopsis pilosula, 20g of Astragalus membranaceus, 9g of Ligustrum lucidum, 6g of Epimedium, 10g of Prunella vulgaris, 6g of Rhizoma Cyperi, 6g of Pinellia ternata, 6g of Curcuma zedoaria, 12g of Lithospermum officinale, 20g of Cyperus rotundus, 6g of Curcuma aromatica, and 9g of Albizia julibrissin, for a total of 122g, in triplicate. Add water and decoct twice. According to Table 4, the water addition amount was tested, with the first decoction for 2.0 hours and the second decoction for 1.5 hours. The decoction was filtered, and the filtrate was concentrated under reduced pressure and fixed to 1000ml. The dry paste yield of the different water addition amounts was measured.

[0089] The dry cream yield was determined using the same method as above. The results are shown in Table 4.

[0090] Table 4 Results of water addition

[0091]

[0092] The experimental results show that: taking the dry paste yield as the examination indicator, the dry paste yield of adding 10.8 times the amount of water is not much different from the dry paste yield of adding 8.6 times the amount of water. The dry paste yield of adding 8.6 times the amount of water is the highest, so it is chosen to add 8 times the mass of water for the first time and 6 times the mass of water for the second time.

[0093] 1.3.4 Examination of decoction time

[0094] Weigh the following Chinese herbal medicine slices according to the prescription ratio: 12g of Codonopsis pilosula, 20g of Astragalus membranaceus, 9g of Ligustrum lucidum fruit, 6g of Epimedium, 10g of Prunella vulgaris, 6g of Rhizoma Cyperi, 6g of Pinellia ternata, 6g of Curcuma zedoaria, 12g of Lithospermum officinale, 20g of Cyperus rotundus, 6g of Curcuma aromatica, and 9g of Albizia julibrissin bark, for a total of 122g, in triplicate. Decoction was performed twice, and the test was performed according to Table 5, with 8 times the weight of water added the first time and 6 times the weight of water added the second time. The decoction extract was filtered, concentrated under reduced pressure, and the volume was fixed to 1000ml. The dry paste yield at different decoction times was measured.

[0095] The dry cream yield was determined using the same method as above. The results are shown in Table 5.

[0096] Table 5 Results of the decoction time

[0097]

[0098] The experimental results show that: taking the dry paste yield as the examination indicator, the dry paste yield is not much different. Considering time and energy saving, we chose to add water and boil it twice. The first time, 8 times the mass of water was added and boiled for 2.0 hours; the second time, 6 times the mass of water was added and boiled for 1.5 hours.

[0099] 1.4 Selection of concentration and drying process conditions

[0100] 1.4.1 Investigation of the density of thick paste

[0101] According to the prescription, the following Chinese medicinal pieces were weighed: 12g of Codonopsis pilosula, 20g of Astragalus membranaceus, 9g of Ligustrum lucidum fruit, 6g of Epimedium, 10g of Prunella vulgaris, 6g of Rhizoma Cyperi, 6g of Pinellia ternata, 6g of Curcuma zedoaria, 12g of Lithospermum officinale, 20g of Cyperus scutellariae, 6g of Curcuma aromatica, and 9g of Albizia julibrissin bark, for a total of 122g, in 5 portions of each. The pieces were decocted twice, with 12 times the weight of water added the first time and 10 times the weight of water added the second time. The extract was filtered and the filtrate was concentrated under reduced pressure to produce extracts of varying densities. These extracts were then mixed with dextrin in a 1:1 ratio to form a soft material. The extracts were then sieved through a 12-mesh sieve for extrusion and granulation. The extracts were then dried in a vacuum drying oven at 70°C for 30 minutes, removed, cooled, and sieved through a 12-mesh sieve for granulation. The results are shown in Table 6.

[0102] Table 6 Investigation of the density of thick paste

[0103]

[0104] The experimental results show that the particles concentrated to a thick paste with a relative density of about 1.20 to 1.25 have good formability and appearance.

[0105] 1.4.2 Investigation of Concentration Conditions

[0106] Weigh the following Chinese medicinal pieces according to the prescribed ratio: Codonopsis pilosula 12g, Astragalus membranaceus 20g, Ligustrum lucidum fruit 9g, Epimedium brevicornum 6g, Prunella vulgaris 10g, Rhizoma Cyperi 6g, Pinellia ternata 6g, Curcuma 6g, Lithospermum officinale 12g, Cyperus rotundus 20g, Curcuma aromatica 6g, and Albizia julibrissin bark 9g, for a total of 122g, in 3 portions of each. Decoction was performed twice: the first time with 12 times the weight of water and simmered for 1.5 hours; the second time with 10 times the weight of water and simmered for 1.0 hour. The decoction was filtered through a 200-mesh filter and concentrated under reduced pressure. Concentration conditions were: vacuum of -0.06 to -0.08 MPa, temperatures of 50-60°C, 60-70°C, and 70-80°C. The optimal concentration temperature was determined, with concentration to a relative density of 1.25. The time to completion of concentration and the presence of foaming during the concentration process were used as evaluation criteria. The results are shown in Table 7.

[0107] Table 7 Concentration Conditions Investigation Table

[0108]

[0109] The experimental results show that: Experiments 1 and 2 take a long time, and although the temperature of Experiment 3 is higher, the time is shorter and it is easy to foam. Therefore, the concentration conditions are selected as: temperature 60-70℃, relative density about 1.20-1.25 (60℃).

[0110] 1.4.3 Investigation of drying conditions

[0111] According to the prescription ratio, weigh the following Chinese herbal medicine slices: 12g of Codonopsis pilosula, 20g of Astragalus membranaceus, 9g of Ligustrum lucidum, 6g of Epimedium, 10g of Prunella vulgaris, 6g of Rhizoma Cyperi, 6g of Pinellia ternata, 6g of Curcuma zedoaria, 12g of Lithospermum officinale, 20g of Cyperus rotundus, 6g of Curcuma aromatica, and 9g of Albizia julibrissin, for a total of 122g, 3 portions each. Add water and decoct twice, adding 12 times the weight of water for the first time and decocting for 1.5 hours; adding 10 times the weight of water for the second time and decocting for 1.0 hour. The decoction was filtered through a 200-mesh filter, concentrated under reduced pressure, fixed to 1000ml, and dried under the following conditions. The drying completion time, drying phenomenon, and solubility were used as the investigation indicators, and the appropriate drying conditions were selected. The results are shown in Table 8.

[0112] Table 8 Drying condition investigation table

[0113]

[0114] The results showed that the weights of the dry pastes obtained in the three different experiments were 27.32g, 27.50g and 27.41g respectively, but the drying time in Experiment 1 was longer; the drying time in Experiment 3 was shorter and there was bubbling. At the same time, considering that high temperature can easily destroy the effective ingredients in the dry paste, the drying conditions of this product are tentatively set as a temperature of 65-70℃ and a vacuum degree of -0.06MPa to -0.08MPa.

[0115] The concentration and drying conditions of this product are: concentrated under reduced pressure (temperature 60-70°C, vacuum degree -0.06MPa to -0.08MPa) to a thick paste with a relative density of 1.20-1.25 (measured at 60°C), and then vacuum dried (temperature 65-70°C, vacuum degree -0.06MPa to -0.08MPa).

[0116] 1.5 Research on molding process

[0117] 1.5.1 Selection of excipient types

[0118] This product is a compound preparation, extracted using a fully aqueous process. The resulting extract powder has relatively good solubility, but is highly hygroscopic, with poor fluidity and compressibility. Suitable excipients are required to improve the extract powder's properties. The type of diluent is a key factor influencing product quality. The following factors determined the choice of starch and dextrin for this study. Softening, granulation, drying, and solubility were used as evaluation criteria to determine the appropriate excipient type.

[0119] (1) For granules, the excipients selected should have good formability, good water solubility and low hygroscopicity;

[0120] (2) The selected excipients are all commonly used excipients for granules, and their properties will not cause adverse interactions with drugs and will not affect drug testing;

[0121] (3) The selected excipients have pharmaceutical standards;

[0122] Three portions of dry paste (50 g each) were weighed, and 50 g of starch, dextrin, and lactose were added, respectively. The mixture was pulverized and mixed uniformly. The mixture was then softened with 90% by volume ethanol and granulated with a 12-mesh sieve. The mixture was dried at 40-50°C and granulated with a 12-mesh sieve. The optimal amount of excipients was determined by evaluating the stickiness of the softening material, the clogging of the granulation screen, the agglomeration during drying, the granulation quality, and the taste. The results are shown in Table 9.

[0123] Table 9 Selection test results of excipient types

[0124]

[0125] The test results show that within the scope of the experimental design, compared with the three auxiliary materials, dextrin does not block the screen during the granulation process, is easy to granulate after drying, has uniform granules and good solubility, so dextrin is selected as the auxiliary material for this product.

[0126] 1.5.2 Selection of auxiliary material dosage

[0127] According to Table 5, 25 g of each of 4 dry pastes were weighed, and the weight of the dextrin in the table below was weighed respectively. After mixing, 90% volume fraction ethanol was used to make a soft material, and 12 mesh sieve was used for granulation. The materials were dried at 60 ° C, and granulated with a 12 mesh sieve. The evaluation indicators were whether the soft material was sticky, whether the granulation blocked the sieve, whether the drying was agglomerated, the granulation condition, taste, and granule yield. The most suitable amount of excipients was selected. The results are shown in Table 10.

[0128] Table 10 Ratio of dry paste and auxiliary materials

[0129]

[0130] Table 11 Effects of different formulations on granulation and granule quality

[0131]

[0132] Experiments show that as the amount of excipients increases, the granulation process becomes better. When the ratio of excipients to dry paste is 1:1.25, the granulation process can meet the requirements. Therefore, the ratio of dry paste to dextrin is selected as 1:1.25.

[0133] 1.5.3 Selection of flavoring agent dosage

[0134] Because this preparation has a bitter taste, a certain amount of sweetener or flavoring agent should be added to improve patient compliance and medication use. In granules, the most commonly used excipient, sucrose, serves as both a diluent and a sweetener. However, its use as an excipient is restricted by many elderly individuals and those who abstain from sugar. Therefore, steviol glycosides were selected as the flavoring agent for this product.

[0135] Stevioside is a mixture primarily composed of stevioside, which is approximately 300 times sweeter than sucrose. As a non-caloric sweetener, stevioside has been shown to lower blood pressure, promote metabolism, and treat hyperacidity, making it suitable for this preparation. The optimal stevioside dosage is determined based on taste.

[0136] Weigh three portions of dry paste and dextrin at a ratio of 1:1.25 and mix thoroughly. Dissolve the stevioside in 90% ethanol by volume to form a soft base. Granulate with a 12-mesh sieve, dry at 60°C, and re-grind with a 12-mesh sieve. The optimal dosage was determined based on mouthfeel. Results are shown in Table 12.

[0137] Table 12 Ratio of dry paste and auxiliary materials

[0138]

[0139] The experimental results show that within the scope of the experimental design, taking taste as the evaluation index, the taste of formula 2 is suitable, so the dosage of steviol glycosides in this product is 0.3%.

[0140] 1.5.3 Selection of wetting agent type and examination of concentration

[0141] Commonly used wetting agents for granules include water and ethanol with different volume fractions. However, the dry paste powder of this preparation contains a large amount of sticky components such as sugars, which easily clump when exposed to water, making the soft material too sticky and difficult to granulate. Therefore, we used ethanol as the wetting agent and used the particle qualification rate and granulation condition as indicators to optimize ethanol with different volume fractions through single-factor experiments.

[0142] Three portions of the mixed powder, 100 g each, were prepared according to the established formula. 70%, 75%, and 80% ethanol (volume fractions) were used as wetting agents. The soft material was squeezed through a 12-mesh sieve, dried at 45-50°C, and sieved through a 12-mesh sieve. The granulation, granulation, and dry granule condition were observed. The results are shown in Table 13.

[0143] Table 13 Selection results of wetting agent concentration

[0144]

[0145]

[0146] The experimental results show that within the experimental design range, when the ethanol concentration is 75%, the granule yield is the highest, the granulation is easy, and the granules are uniform in color. Therefore, 75% volume fraction ethanol is selected as the wetting agent for this product.

[0147] 1.5.4 Wetting agent dosage examination

[0148] Five portions of the mixed powder were weighed according to the established formula, each 100 g. 75% (volume fraction) ethanol was used as a wetting agent in amounts of 20 ml, 25 ml, 30 ml, 35 ml, and 40 ml, respectively. The soft material was squeezed through a 12-mesh sieve, dried at 40-50°C, and sieved through a 12-mesh sieve. The granulation, granulation, and dry granule condition were observed. The results are shown in Table 14.

[0149] Table 14 Selection results of wetting agent dosage

[0150]

[0151] The experimental results show that within the experimental design range, when the dosage of 75% volume fraction ethanol is 25-30ml, considering the granulation process, particle yield and particle qualification rate, all the inspection indicators are good. Therefore, this product selects 75% volume fraction ethanol as the wetting agent, and the dosage is 25%-300%.

[0152] 1.5.5 Mixing time investigation

[0153] Weigh 100g of dry paste powder each, a total of 3 parts, add appropriate amount of dextrin to each part and stir for 5 minutes, 10 minutes and 15 minutes respectively, then spray with 75% volume fraction ethanol as a wetting agent, stir to make a soft material, wet granulate, dry, and granulate. The appearance of the drug-excipient mixed powder, the condition of the soft material and the appearance of the particles are used as evaluation indicators to investigate the optimal drug-excipient stirring time. The results are shown in Table 15.

[0154] Table 15 Mixing time investigation

[0155]

[0156] The experimental results show that the mixing time of dry paste powder and dextrin is 10 minutes to 15 minutes, and the color uniformity of the prepared mixed powder, soft material and granules is good. Therefore, the mixing time of the auxiliary drug in the preparation process of this product is 10 minutes to 15 minutes.

[0157] 1.5.6 Determination of angle of repose

[0158] The fluidity of particles was investigated by measuring the angle of repose. The fixed funnel method was used. Three funnels were connected in series and fixed on an iron stand. Weighing paper (labeled coordinates) was placed horizontally below the funnels. The lowest end of the funnel was at a certain height (H) from the weighing paper. The particles were carefully poured into the top funnel along the wall of the funnel until the tip of the particle cone formed by the bottom funnel on the weighing paper touched the funnel mouth. The diameter of the cone bottom was measured from the coordinates of the weighing paper. The measurement was repeated 5 times. The angle of repose was calculated according to Tana=H / R. The results are shown in Table 16.

[0159] Table 16 Particle repose angle measurement results

[0160]

[0161] Conclusion: As can be seen from the table, the average repose angle of the five groups of particles is 12.74, which is less than 40., indicating that the particles of this product have good fluidity.

[0162] 1.5.7 Determination of molding process

[0163] (1) Molding process

[0164]

[0165] (2) Molding process conditions

[0166] Preparation of soft material: dry paste powder: dextrin (1:1.25), granulated with 75% volume fraction ethanol, the dosage is about 25-30% of the total amount of dry paste powder + auxiliary materials.

[0167] Granulation: Use the extrusion screening method to granulate, and it is best to choose a 12-mesh screen.

[0168] Granule drying: The wet granules are dried at 60℃. The degree of drying should be such that the moisture content is controlled below 8%.

[0169] Whole grain: Use 12 mesh sieve to whole grain.

[0170] 1.5.8 Dosage Conversion

[0171] The daily dosage of this product is approximately 165g. The water extraction yield of dry paste is 16.30%, resulting in a daily dry paste dosage of 26.9g. Add 33.60g of excipients at a dry paste:excipient ratio of 1:1.25, and approximately 64g of granules are prepared. If taken twice daily, 64 / 2 = 32g per dose, so the packaging specification for this product is 8.0g / bag.

[0172] Dosage and Administration: Oral administration. 32g at a time, twice a day; or as directed by a physician.

[0173] 1.5.9 Pilot Process Studies

[0174] To examine process stability, three batches of samples were prepared using the optimized process (scaled up by at least 10 times the prescribed amount). The preparation equipment list is shown in Table 17. The three batches of pilot products were tested according to the proposed quality standards (draft). The relevant process parameters and test results are shown in Table 18.

[0175] Table 17 Pilot Equipment List

[0176] Device Name Device Model Equipment Manufacturer Chinese medicine extraction tank <![CDATA[YT-0.5m 3 ]]> Zhejiang Kaidi Pharmaceutical Machinery Co., Ltd. Single-effect external circulation concentrator YZNS-200 Zhejiang Kaidi Pharmaceutical Machinery Co., Ltd. vacuum drying oven FZG-15 Nanjing Aoding Machinery Equipment Co., Ltd. vacuum drying oven FZG-15 Nanjing Ruibang Pharmaceutical Equipment Co., Ltd. Water-cooled grinder 30B Nanjing Ruibang Pharmaceutical Equipment Co., Ltd. Trough mixer CH-100 Nanjing Ruibang Pharmaceutical Equipment Co., Ltd. Swing pellet machine YK-160 Nanjing Ruibang Pharmaceutical Equipment Co., Ltd. Hot air circulation oven CT-CI Nanjing Ruibang Pharmaceutical Equipment Co., Ltd. Three-dimensional mixer SYH-200 Nanjing Ruibang Pharmaceutical Equipment Co., Ltd. Granule automatic packaging machine DXDK-40VI Tianjin Hanton Food Machinery Co., Ltd.

[0177] Table 18 Technical data of three batches of pilot production

[0178]

[0179]

[0180] Conclusion: The results of three pilot tests showed that the process was stable and feasible and suitable for mass production.

[0181] 1.6 Process Summary

[0182] Twelve herbs, including Codonopsis pilosula and Astragalus membranaceus, were decocted twice with water. The first decoct was performed with 8 times the weight of water, and the decoct was extracted for 2.0 hours, filtered. The second decoct was performed with 6 times the weight of water, and the decoct was extracted for 1.5 hours, filtered, and the filtrates were combined and concentrated under reduced pressure to a clear paste with a relative density of approximately 1.05-1.10 (at 60°C). The decoct was vacuum-dried and pulverized into a fine powder. Appropriate amounts of dextrin and steviol glycoside were added, mixed, and granulated with 75% by volume ethanol. The powder was dried and packaged in 1000g bags (8g / bag). The results of three pilot batches of samples showed that the process was generally stable.

[0183] 1.7 Sources and quality standards of excipients

[0184] Dextrin: should comply with the relevant provisions of dextrin under Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China

[0185] Stevioside: It should comply with the relevant provisions under dextrin in Part IV of the 2020 edition of the Pharmacopoeia of the People's Republic of China.

[0186] 2. Draft quality standards for preparations and drafting instructions:

[0187] 2.1 Draft Quality Standards for Pharmaceutical Preparations

[0188] Fuzhengtiaoqijiedu granules

[0189] [Prescription] See Example;

[0190] [Preparation method] See the embodiment;

[0191] [Properties] This product is brown to tan granules.

[0192]

Identification

[0193] (2) Weigh three portions of Fuzheng Tiaoqi Jiedu Granules, weigh 10 g each, add 150 ml of water, boil for 30 min, filter, adjust the pH of the filtrate to 2-3 with hydrochloric acid, and extract three times with 20 ml of ether by shaking. Combine the ether solutions, evaporate to dryness, and dissolve the residue in 1 ml of anhydrous ethanol to prepare the test solution. Separately, weigh 3 g of Prunella Vulgaris control medicinal material and 6 g of Lithospermum officinale control medicinal material, add 30 ml of 70% volume fraction ethanol solution, sonicate for 30 min, filter, evaporate the filtrate to dryness, and dissolve the residue in 1 ml of anhydrous ethanol to prepare the control medicinal material solution. According to the thin layer chromatography method (General Rules 0502 of Part IV of the 2020 edition of the Chinese Pharmacopoeia), 15 μl of each of the three solutions were taken and spotted on the same silica gel G thin layer plate, and toluene (water saturated)-ethyl acetate-formic acid (8:4:1.2) was used as the developing agent. The plate was developed, taken out, dried, sprayed with 5% ferric chloride ethanol solution, heated at 105°C until the spots were clearly colored, and inspected under sunlight.

[0194] (3) Weigh three portions of Fuzheng Tiaoqi Jiedu Granules, weigh 30g each, add 50ml of methanol, sonicate for 30min, filter, add petroleum ether (30-60℃) to the filtrate and shake and extract twice, 50ml each time, combine the petroleum ether (30-60℃) solution, evaporate to dryness, add 0.5ml of methanol to the residue to dissolve it, and use it as the test solution. Weigh 5g of Curcuma Radix control medicinal materials and 1g of Curcuma zedoaria control medicinal materials, prepare them in the same way as the test sample, and use them as the control medicinal material solution. According to the thin layer chromatography method (General Rules 0502 of Part Four of the 2020 edition of the Chinese Pharmacopoeia), take 10μl of Curcuma Radix control medicinal material solution, 1μl of Curcuma zedoaria control medicinal material, and 30μl of sample solution, use n-hexane-ethyl acetate (17:3) as the developing solvent, develop, take out, dry, spray with 10% sulfuric acid ethanol solution, heat at 105℃ until the spots are clearly colored, and inspect under sunlight.

[0195] Others should comply with the relevant provisions under granules (General Rules 0102, Part IV, 2020 Edition of the Chinese Pharmacopoeia).

[0196] [Function and Indications] Strengthens the body and regulates Qi, dissipates stagnation and detoxifies; mainly treats breast cancer, thyroid cancer, and breast or neck lumps caused by thyroid nodules

[0197] [Usage and Dosage] Oral administration, one pack at a time, three times a day.

[0198]

Specification

[0199]

Storage

[0200]

Validity period

[0201] 2.2 Drafting Instructions for the Draft Quality Standard for Fuzheng Tiaoqi Jiedu Granules

[0202] [Name] Fuzheng Tiaoqi Jiedu Granules are named according to the original research unit, therapeutic effects and dosage form.

[0203] [Prescription] This product is based on an empirical formula. The Chinese medicinal materials in this formula all comply with the relevant regulations for each medicinal material decoction piece in Part I of the 2020 edition of the Chinese Pharmacopoeia.

[0204] [Preparation] The preparation method of this product was formulated by optimizing the optimal process conditions through single-factor experiments, studying the molding process and accumulating relevant parameters of the process technical conditions of three batches of pilot samples. For details, please refer to the process research materials.

[0205]

Properties

[0206]

Identification

[0207] (2) Thin layer identification of Prunella vulgaris and Lithospermum officinale: Figure 8This is a TLC identification chart of Prunella Vulgaris and Lithospermum officinale for treating breast and thyroid nodules and cancerous granules, as described in the Examples. Thin-layer chromatography (TLC) results demonstrate good TLC separation and clear spots. To verify its specificity, appropriate amounts of Prunella Vulgaris, Lithospermum officinale, and other medicinal ingredients lacking Prunella Vulgaris and Lithospermum officinale were weighed according to the prescription ratio. Negative samples lacking Prunella Vulgaris, Lithospermum officinale, and Prunella Vulgaris and Lithospermum officinale were prepared according to the preparation method. Negative sample solutions lacking Prunella Vulgaris, Lithospermum officinale, and Prunella Vulgaris and Lithospermum officinale were also prepared using the same method for preparing the test solution. Following TLC separation using the same method, the negative sample chromatogram showed no spots of the same color at the corresponding positions in the control herbal chromatogram, indicating the absence of negative interference and specificity.

[0208] (3) Thin layer identification of Curcuma and Curcuma. The results of the thin layer test showed that the TLC separation effect was good and the spots were clear. To verify its specificity, appropriate amounts of the other medicinal ingredients of Curcuma, Curcuma, Curcuma and Curcuma were weighed according to the prescription ratio, and negative samples of Curcuma, Curcuma and Curcuma were prepared according to the preparation method. The negative sample solutions of Curcuma, Curcuma, Curcuma and Curcuma were prepared in the same way as the test solution. After thin layer separation by the same method, there were no spots of the same color in the chromatogram of the negative sample at the corresponding position with the chromatogram of the control medicinal material, indicating that there was no negative interference and it had specificity.

[0209] [Inspection] Three batches of samples were inspected for moisture, particle size, solubility, and microbial limits, and all indicators were in compliance with relevant regulations.

[0210] [Functions and indications] Same as the main text.

[0211] [Usage and dosage] Same as the main text.

[0212] [Storage] Same as the main text.

[0213] Reference: Chinese Pharmacopoeia. Volume 1[S].2020

[0214] 3. Clinical trials

[0215] The granule prescription in this application is rigorous and scientifically compatible, and has a clear therapeutic effect on breast, thyroid nodules and canceration. In order to observe the clinical effect of this granule on breast nodules and canceration, we observed 60 patients with breast nodules and were divided into 2 groups by randomized double-blind method, namely a control group and a treatment group, with 30 examples in each group. The treatment group: took Fuzheng Tiaoqi Jiedu Granules, 1 pack each time, 3 times a day. 28 days is a course of treatment. The control group: routinely gave Xiaojin Capsule orally, 2g each time, 2 times a day, and 28 days is a course of treatment. Observation indicators mainly include: breast nodule efficacy, breast pain before and after treatment, lump size integral, maximum diameter and nodule volume, serum marker levels (CEA, CA-153), safety indicators (adverse event incidence, laboratory index abnormalities).

[0216] The results showed that the total effective rate of breast nodules in the treatment group was 93.3% (28 / 30), and that in the control group was 70% (21 / 30), which was significantly higher in the treatment group than in the control group (P < 0.05); compared with before treatment, breast pain, lump size, maximum diameter and volume of nodules, CEA and CA-153 levels in the two groups were significantly reduced after treatment (P < 0.05), and those in the treatment group were significantly lower than those in the control group (P < 0.05); no obvious adverse reactions occurred during the treatment in both groups.

[0217] 3.1 Comparison of the therapeutic efficacy of breast nodules between the two groups

[0218] The results showed that 28 cases in the treatment group were effective and 2 cases were ineffective, with an effective rate of 93.3%; 21 cases in the control group were effective and 9 cases were ineffective, with an effective rate of 70% (P < 0.05). The total effective rate of breast nodules in the treatment group was significantly higher than that in the control group (P < 0.05), see Table 19.

[0219] Table 19 Comparison of therapeutic effects on breast nodules in two groups of patients

[0220]

[0221] 3.2 Comparison of breast pain and lump size scores before and after treatment between the two groups

[0222] The results showed that the breast pain scores before and after treatment in the treatment group were 15.62±2.11 and 8.73±0.92, respectively, while those in the control group were 16.57±2.42 and 12.25±1.86, respectively (P<0.05); the lump size scores before and after treatment in the treatment group were 3.37±0.44 and 1.53±0.24, respectively, while those in the control group were 3.32±0.41 and 2.79±0.36, respectively (P<0.05), and both scores in the treatment group were significantly lower than those in the control group (P<0.05), see Table 20.

[0223] Table 20 Comparison of breast pain and lump size scores before and after treatment in the two groups of patients

[0224]

[0225] 3.3 Comparison of maximum nodule diameter and nodule volume before and after treatment in the two groups

[0226] The results showed that the maximum diameters of the nodules in the treatment group before and after treatment were 1.93±0.35 and 0.75±0.12, respectively, and those in the control group were 1.90±0.41 and 1.38±0.26, respectively (P<0.05); the tumor size scores in the treatment group before and after treatment were 2.14±0.36 and 0.63±0.15, respectively, and those in the control group were 2.12±0.40 and 1.82±0.35, respectively (P<0.05), and both the values ​​in the treatment group were significantly lower than those in the control group (P<0.05), see Table 21.

[0227] Table 21 Comparison of maximum diameter and volume of nodules before and after treatment in the two groups of patients

[0228]

[0229] 3.4 Comparison of CEA and CA-153 levels before and after treatment in the two groups

[0230] The results showed that the CEA levels in the treatment group before and after treatment were 11.72±2.33 and 4.81±0.92, respectively, while those in the control group were 10.28±2.21 and 9.83±1.96, respectively (P<0.05); the CA-153 levels in the treatment group before and after treatment were 75.44±11.92 and 22.51±4.66, respectively, while those in the control group were 72.95±12.21 and 60.24±10.31, respectively (P<0.05), and both levels in the treatment group were significantly lower than those in the control group (P<0.05), see Table 22.

[0231] Table 22 Comparison of CEA and CA-153 levels before and after treatment in the two groups of patients

[0232]

[0233]

[0234] 4. Cell experiments

[0235] This study investigated the effects of Fuzheng Tiaoqi Jiedu Granules on the invasion and migration of breast cancer 4T1 cells. The CCK-8 assay was used to assess the effects of the drugs on cell proliferation and screen the appropriate concentrations for each drug. Corticosterone (CORT) was used to simulate an in vivo stress environment. Cell invasion and migration were assessed using wound healing and Transwell assays. Clonogenicity assays were used to assess cell colony formation. CXCR4 protein expression was assessed using Western blot.

[0236] Results: Fuzheng Tiaoqi Jiedu Granules enhanced the proliferation of MC3T3-E1 cells, increased ALP activity in MC3T3-E1 cells, promoted calcium deposition in MC3T3-E1 cells, inhibited CXCL12, PTHrP, IL-6, and TNF-α levels in the co-culture system, promoted OPG protein expression in MC3T3-E1 cells, and inhibited RANKL protein expression. The CXCR4 agonist CTCE-0214 reversed these experimental results.

[0237] 4.1 Fuzheng Tiaoqi Jiedu Granules significantly inhibited the proliferation of 4T1 cells

[0238] The CCK-8 assay results showed that compared with the control group, the viability of 4T1 cells in the CORT group increased (P < 0.05), and the proliferation rates of the two groups were approximately 24%. Compared with the CORT group, 5%, 10%, and 15%-GBXY and Capecitabine significantly inhibited the proliferation of 4T1 cells (P < 0.05). Figure 1 ;

[0239] Figure 1 Effects of Fuzheng Tiaoqi Jiedu Granules on 4T1 cell viability, **P<0.01vs Control group, #P<0.05vs CORT group, ##P<0.01vs CORT group.

[0240] The results of the clone formation experiment showed that the number of 4T1 cell clones formed in the Control group was larger. Compared with the Control group, the number of 4T1 cell clones formed in the CORT group was significantly increased (P < 0.05). Compared with the CORT group, the clone formation of 4T1 cells was significantly inhibited after 14 days of treatment with 5%, 10%, and 15%-GBXY and Capecitabine (P < 0.05). This further suggests that Fuzheng Tiaoqi Jiedu Granules can effectively inhibit the proliferation of breast cancer cells. Figure 2 .

[0241] Figure 2 This is the effect of Fuzheng Tiaoqi Jiedu Granule on 4T1 cell clone formation, **P<0.01 vs Control group, ##P<0.01 vs CORT group.

[0242] 4.2 Fuzheng Tiaoqi Jiedu Granules effectively inhibited the migration and invasion ability of 4T1 cells

[0243] like Figure 3As shown in the figure, the growth state and migration ability of 4T1 cells in the Control group were good, and the scratch gradually narrowed over time, indicating that 4T1 cells have strong migration ability. Compared with the Control group, the migration ability of 4T1 cells in the CORT group was enhanced (P < 0.05). Compared with the CORT group, 5%, 10%, and 15%-GBXY and Capecitabine significantly inhibited the migration ability of 4T1 cells (P < 0.05); among them, the migration ability of cells in each group did not change at 0h, cell migration was visible at 12h, and the migration of cells in the drug intervention group was slow at 24h, and the scratch was wider than that in the model group. For details, see Figure 3 ;

[0244] Figure 3 This shows the effect of Fuzheng Tiaoqi Jiedu Granules on the migration ability of 4T1 cells. In the figure, A is the 4T1 cell migration graph; B is the cell migration bar graph; **P<0.01 vs Control group, ##P<0.01 vs CORT group.

[0245] like Figure 4 As shown, the number of 4T1 cells at the bottom of the chamber in the Control group was higher. Compared with the Control group, the number of cells at the bottom of the chamber in the CORT group increased (P < 0.05). Compared with the CORT group, the number of cells at the bottom of the chamber in the 5%, 10%, and 15%-GBXY groups and the Capecitabine group was significantly reduced (P < 0.05). In summary, it is suggested that Fuzheng Tiaoqi Jiedu Granules can inhibit the migration and invasion of 4T1 cells. Figure 4 ;

[0246] Figure 4 Effect of Fuzheng Tiaoqi Jiedu Granules on the invasion ability of 4T1 cells. In the figure, A is the 4T1 cell invasion graph; B is the cell invasion bar graph; **P<0.01vs Control group, ##P<0.01vs CORT group.

[0247] 4.3 Effect of Guben Xiaoyan Formula on CXCR4 Protein Expression in 4T1 Cells

[0248] like Figure 5 As shown in Figure 3, compared with the Control group, the expression of CXCR4 protein in 4T1 cells in the CORT group was increased (P < 0.05). Compared with the CORT group, the expression of CXCR4 protein in 4T1 cells in the 5%, 10%, 15%-GBXY and Capecitabine groups was decreased (P < 0.05), indicating that Fuzheng Tiaoqi Jiedu Granules can inhibit the expression of CXCR4 protein. Figure 5 ;

[0249] Figure 5This is the effect of Fuzheng Tiaoqi Jiedu Granule on CXCR4 protein expression in 4T1 cells. In the figure, A is the CXCR4 protein expression graph; B is the CXCR4 protein expression bar graph; **P<0.01vs Control group, #P<0.05vs CORT group, ##P<0.01vs CORT group.

[0250] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A method for preparing particles for treating breast and thyroid nodules and cancerous changes, characterized by: The following steps are involved: S1. Raw material preparation: according to the mass ratio, prepare 199g of Codonopsis pilosula, 332g of Astragalus membranaceus, 149g of Ligustrum lucidum fruit, 100g of Epimedium, 166g of Prunella vulgaris, 100g of Rhizoma Cyperi, 100g of Pinellia ternata, 100g of Curcuma zedoaria, 199g of Lithospermum officinale, 332g of Cyperus rotundus, 100g of Curcuma aromatica, and 149g of Albizia julibrissin bark; S2. Decoction the above twelve ingredients twice with water, adding 8 times the weight of water for the first decoction, extract for 2.0 hours, and filter. S3, add 6 times the mass of water for the second time, extract for 1.5 hours, filter, and combine the filtrate; S4, concentrating under reduced pressure to a clear paste having a relative density of 1.05 to 1.10 at 60°C; S5. Vacuum drying, crushing into fine powder, adding dextrin and 10 g of steviol glycoside, mixing, granulating with 75% volume fraction ethanol, drying, making into 1000 g, and packaging.

2. The method for preparing particles for treating breast and thyroid nodules and cancerous changes according to claim 1, characterized in that: The packaging described in S5 is 8g / bag.

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