Application of Jufengjing in preparation of medicine for treating mammary gland hyperplasia

Abstract

The present application belongs to the technical field of medicine, and particularly relates to application of Ju Fengjing in preparation of medicine for treating mammary gland hyperplasia. Clinical test proves that the total effective rate of Ju Fengjing in treating mammary gland hyperplasia reaches 94%, and meanwhile, the medicine can effectively relieve hardness, pain and tenderness of lumps, improve mammary gland texture, and has a remarkable anti-mammary gland hyperplasia effect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of Chufeng Essence in the preparation of drugs for treating breast hyperplasia. Background Technology

[0002] The essence of *Childhood Phoenix Essence* has the effects of warming and tonifying kidney yang, replenishing qi and nourishing blood. It is used for lower back pain, weakness in the limbs, dizziness and tinnitus, neurasthenia and insomnia, palpitations, memory loss, loss of appetite, and menstrual disorders in women caused by kidney yang deficiency and qi and blood deficiency. The applicant's previous research has confirmed that *Childhood Phoenix Essence* has significant efficacy in treating thin endometrium, increasing endometrial thickness, improving uterine artery blood supply, and alleviating kidney yang deficiency.

[0003] The main symptoms of mammary hyperplasia are breast lumps and cyclical pain. Some patients may also experience nipple discharge, irregular menstruation, and personality changes. The incidence of mammary hyperplasia is increasing year by year, the course of the disease is relatively long, and the age of onset is gradually decreasing. A small number of cases of mammary hyperplasia may develop into atypical hyperplasia or even be complicated by breast tumors, seriously affecting the physical and mental health of patients.

[0004] Western medicine believes that breast hyperplasia is related to elevated estrogen levels in breast tissue or abnormal estrogen receptor content in fibroblasts. Therefore, it often uses hormonal drugs and analgesics for symptomatic treatment. Western medicine treatments include tamoxifen and bromocriptine. Tamoxifen competitively inhibits endogenous estrogen and has a good relieving effect on breast pain; however, long-term use may cause adverse reactions such as endometrial thickening and menstrual disorders. Bromocriptine is a specific hypothalamic and pituitary dopamine receptor agonist that acts directly on the anterior pituitary gland to inhibit prolactin secretion. However, its use requires exclusion of primary or secondary hyperprolactinemia, as well as nipple discharge not caused by simple breast hyperplasia, such as intraductal papilloma. Although the above drugs can effectively improve symptoms, the treatment period is long, the recurrence rate is high, and there is a high risk of adverse reactions.

[0005] In Traditional Chinese Medicine (TCM) theory, this condition is called "mastopathy." The Qing Dynasty physician Gao Bingjun, in his *Collection of Experiences in Ulcer Treatment* (specifically, the section on "Distinguishing Mammary Hyperplasia, Breast Phlegm, and Breast Cancer"), recorded: "There are nodules in the breast, shaped like balls or eggs, without pain or fever, and the skin color remains unchanged. The size of the nodule fluctuates with mood; this is called mastopathy." This summarizes the characteristics of mastopathy. *Danxi's Heart Method* states: "The breast is governed by the Yangming meridian, while the nipple belongs to the Jueyin meridian." The nipple is associated with the liver, and the breast with the stomach; therefore, in terms of meridians, the liver meridian and the breast have a close physiological and pathological connection. Liver qi stagnation is the most crucial link in the formation of mammary hyperplasia. Therefore, liver qi stagnation, qi stagnation, and blood stasis are the main pathogenesis; thus, treatment should highly emphasize soothing the liver, regulating qi, and promoting blood circulation. According to the TCM syndrome differentiation, breast hyperplasia is divided into three types: liver qi stagnation, Chong and Ren meridian imbalance, and phlegm and blood stasis. The treatment for different types of breast hyperplasia also differs. For liver qi stagnation, medications that soothe the liver, regulate qi, relieve stagnation, and disperse nodules are needed. For Chong and Ren meridian imbalance, medications that tonify the liver and kidneys, regulate the Chong and Ren meridians, and promote qi and blood circulation are needed. For phlegm and blood stasis, medications that promote blood circulation, remove blood stasis, soften and disperse nodules are needed.

[0006] Among them, the Chong and Ren meridian imbalance type is more common in women around menopause. Its main manifestations include breast nodules with dull or throbbing pain, irregular menstrual cycles, worsening pain before menstruation and relief after menstruation, scanty and pale menstrual flow, or even amenorrhea. It is often accompanied by lower back pain, weakness, irritability, fatigue, dizziness, pale tongue with a white coating, and a weak or soggy pulse. Given the problems with existing drugs and treatments for breast hyperplasia, there is an urgent need to explore traditional Chinese medicine that can effectively improve and treat Chong and Ren meridian imbalance type breast hyperplasia, reduce the adverse reactions of existing Western medicine treatments and address the inconsistent efficacy of existing traditional Chinese medicine treatments, thus achieving more effective treatment. Summary of the Invention

[0007] This invention provides the application of *Chūfūjīng* extract in the preparation of drugs for treating breast hyperplasia. Clinical trials have confirmed that *Chūfūjīng* extract has a total effective rate of 94% in treating breast hyperplasia (Chongren imbalance type), and can effectively relieve the hardness, pain, and tenderness of lumps, improve breast texture, and has a good anti-breast hyperplasia effect, providing a new and effective treatment for breast hyperplasia.

[0008] This invention provides the following technical solution:

[0009] Application of Chufeng Essence in the preparation of drugs for treating breast hyperplasia.

[0010] Furthermore, the breast hyperplasia described is a type of breast hyperplasia caused by imbalance of the Chong and Ren meridians.

[0011] Furthermore, the "Young Phoenix Essence" is made from the following ingredients in parts by weight: 6g Amomum villosum, 5g Cinnamomum cassia, 4g Paeonia suffruticosa, 5g Acorus tatarinowii, 7g Aquilaria sinensis, 8g Astragalus membranaceus, 6g Glycyrrhiza uralensis, 4g Ginseng, 3g Deer antler, 9g Paeonia lactiflora, 8g Psoralea corylifolia, 9g Rubus idaeus, 5g Nelumbo nucifera stamens, 8g Lycium barbarum, 14g Alisma plantago-aquatica, 18g Rehmannia glutinosa, 11g Cistanche deserticola, 15g Dioscorea opposita, 6g Angelica sinensis, 5g Achyranthes bidentata, 8g Poria cocos, 5g Epimedium brevicornu, 7g Cynomorium songaricum, 12g Cibotium barometz, 5g Eucommia ulmoides, 75g sheep testicles, 12g sheep penis, and 150g chicken fetus.

[0012] The above-mentioned "Young Phoenix Essence" is prepared using the following steps: 28 medicinal materials of the above-mentioned quality, including Amomum villosum, Cinnamomum cassia, Paeonia suffruticosa, Acorus tatarinowii, Aquilaria sinensis, Astragalus membranaceus, Glycyrrhiza uralensis, Ginseng, Deer antler, Paeonia lactiflora, Psoralea corylifolia, Rubus idaeus, Nelumbo nucifera stamens, Lycium barbarum, Alisma plantago-aquatica, Rehmannia glutinosa, Cistanche deserticola, Dioscorea opposita, Angelica sinensis, Achyranthes bidentata, Poria cocos, Epimedium brevicornu, Cynomorium songaricum, Cibotium barometz, Eucommia ulmoides, sheep testicles, sheep penis, and chicken fetus, are processed, pulverized, percolated with 70% ethanol, the extract is collected, concentrated, diluted with water, bottled, and sterilized.

[0013] Furthermore, the described Chufeng Essence is a pure traditional Chinese medicine oral preparation; the dosage form is oral liquid, powder, granules, pills, tablets or capsules.

[0014] The beneficial effects of the present invention include, but are not limited to:

[0015] This invention relates to the application of Chufengjing (a traditional Chinese medicine) in the treatment of breast hyperplasia, expanding its therapeutic applications and providing a solution to the shortcomings of existing medications and methods for treating breast hyperplasia. Clinical trials have shown that Chufengjing achieves a total effective rate of 93.9% in treating patients with breast hyperplasia, effectively relieving lumps of hardness, pain, and tenderness, improving breast texture, and demonstrating a strong anti-breast hyperplasia effect.

[0016] Analysis of the menstrual flow score scale and the Traditional Chinese Medicine syndrome scoring scale showed that after treatment with Chufengjing, patients experienced significant improvements in menstrual flow, color, and consistency, with statistically significant differences. Furthermore, after treatment, patients showed significant improvements in symptoms such as cold limbs, dull complexion, lower back pain, dizziness, tinnitus, and total symptom scores compared to before treatment, with statistically significant differences. This indicates that Chufengjing is a potentially effective treatment for breast hyperplasia, especially breast hyperplasia caused by imbalance of the Chong and Ren meridians. Detailed Implementation

[0017] To clearly illustrate the technical features of this solution, the invention will be described in detail below through specific embodiments. The scope of this invention is not limited to the following embodiments. Those skilled in the art will understand that various changes and modifications can be made to this invention without departing from its spirit and scope.

[0018] Unless otherwise specified, the instruments, reagents, and materials involved in the following embodiments are all conventional instruments, reagents, and materials that are already available in the prior art and can be obtained through legitimate commercial channels.

[0019] I. Preclinical Research

[0020] 1.1 Summary of Pharmacological Research Experiments

[0021] Seven pharmacological experiments were conducted on Chufengjing (a type of herbal medicine). The results showed that: 1) Chufengjing can improve the coordination and anti-fatigue ability of mice; 2) Continuous gavage for 7 days can prolong the hypoxia tolerance time and reduce oxygen consumption in mice; 3) It can significantly increase the diameter of microvessels in the rat auricle and increase blood flow velocity; 4) It can significantly increase the blood flow in the rat carotid artery; 5) It can improve immune function: enhance the phagocytic function of mouse phagocytes; partially resist the immunosuppressive effect induced by cyclophosphamide (CTX); promote the production of serum hemolysin; and have a significant antagonistic effect on the reduction of plaque-forming cells (PFC) induced by CTX; 6) It can significantly inhibit ADP-induced platelet aggregation in Yang-deficient rats and enhance the body's immune function.

[0022] 1.2.2 Summary of Toxicological Studies

[0023] The acute and long-term toxicity of Chufengjing were studied, and the experimental results showed that Chufengjing is safe to use and has no obvious toxic side effects.

[0024] (1) Acute toxicity

[0025] The dose of Chufengjing was equivalent to 132 times the clinical dose for humans (50 kg). Mice showed no abnormalities in activity, glossy fur, normal stool, and slight weight gain 24 hours and 7 days after administration, indicating that Chufengjing is relatively safe.

[0026] (2) Long-term toxicity

[0027] The dosage of Chufengjing was administered orally at 3 times, 2 times, and 1 times the clinical dose for humans (50 kg). After 60 days of continuous administration to rats, the body weight of all rats increased. No abnormalities were found in white blood cell count, alanine aminotransferase, and blood urea nitrogen. Routine pathological microscopy also revealed no drug-related pathological changes, indicating that long-term use of Chufengjing has no significant toxic effects.

[0028] (3) Reproductive toxicity

[0029] The no-observed-adverse-effect level (NOAEL) of Chufengjing in SD rats via gavage was 30 mL / kg / d, approximately 103.4 times the human clinical dose and approximately 16.7 times the equivalent clinical dose in rats. Oral administration of Chufengjing at doses of 30 mL / kg / d or lower had no significant effect on pregnant SD rat mothers or embryos; fetal development was normal, and no teratogenic effects were observed. This indicates that the maximum no-observed-adverse-effect level (NOAEL) for both the mother and fetus in pregnant SD rats via Chufengjing was 30 mL / kg / d.

[0030] II. Clinical Trials

[0031] 2.1 Purpose of the experiment: To evaluate the efficacy and safety of Chufengjing in treating breast hyperplasia caused by Chongren disorder.

[0032] 2.2 Test Basis

[0033] The trial protocol was developed in accordance with the "Regulations for Drug Registration Management", "Good Clinical Practice for Drug Clinical Trials", "Regulations for Reporting and Monitoring Adverse Drug Reactions", "Guiding Principles for Clinical Research of New Traditional Chinese Medicine for the Treatment of Menstrual Disorders" and "Guiding Principles for Clinical Research of New Traditional Chinese Medicine for the Treatment of Kidney Yang Deficiency Syndrome" edited by Zheng Xiaoyu, "Obstetrics and Gynecology" (8th edition edited by Xie Xing and Gou Wenli) and "Traditional Chinese Medicine Gynecology" (9th edition edited by Ma Baozhang and Qi Cong, 2nd edition edited by Zhang Yuzhen), and relevant pharmacological and toxicological experimental and clinical research data of Chu Feng Jing.

[0034] Traditional Chinese Medicine (TCM) classification of breast hyperplasia: According to the "TCM classification criteria for breast hyperplasia" released at the 8th meeting of the Breast Disease Professional Committee of the Chinese Society of Traditional Chinese Medicine Surgery in 2002, the subjects were divided into three types: liver qi stagnation type, Chong and Ren meridian imbalance type, and phlegm and blood stasis type.

[0035] Symptoms:

[0036] Liver Qi stagnation type: Breast distending pain is cyclical, often aggravated before or during menstruation. Breast lumps may also fluctuate with emotional changes. The distending pain often involves the chest, ribs, axillary line and clavicle line area, accompanied by emotional distress, chest tightness, belching, insomnia, thin white tongue coating, pale red or pale dark tongue body, and thready or wiry pulse.

[0037] Disorders of the Chong and Ren meridians: This type is more common in women around menopause. Symptoms include breast nodules with dull pain or swelling, irregular menstrual cycles, worsening pain before menstruation and relief after menstruation, scanty and pale menstrual flow, or even amenorrhea. It is often accompanied by lower back pain and weakness, irritability, fatigue, dizziness, pale tongue with white coating, and weak or soggy pulse.

[0038] Phlegm and Blood Stasis Intertwined Type: Multiple breast lumps, some of which are strip-shaped, nodular, or bead-like, tough but not hard, mobile and not sticky, some have yellow discharge from the nipple, the pain or stabbing pain of the lumps worsens during menstruation, the tongue coating is greasy and the tongue body is dark purple, the pulse is slippery or thready and hesitant.

[0039] Among them, the treatment theory of breast hyperplasia with Chong and Ren imbalance is consistent with the traditional Chinese medicine treatment theory of warming kidney yang and replenishing qi and blood. Further research should be conducted on the treatment effect of breast hyperplasia with Chong and Ren imbalance.

[0040] 2.3 Diagnostic criteria

[0041] 2.3.1 Diagnostic criteria for breast hyperplasia

[0042] Traditional Chinese Medicine diagnostic criteria: Refer to the "Guidelines for Diagnosis and Treatment of Common Gynecological Diseases in Traditional Chinese Medicine" (ZYYXH / T203~246-2012, 1st Edition, China Traditional Chinese Medicine Press, 2012) issued by the China Association of Traditional Chinese Medicine.

[0043] Western medicine diagnostic criteria: Refer to the diagnostic criteria for breast hyperplasia in the "Clinical Practice Guidelines" (Chinese Medical Association Surgical Branch, 2006):

[0044] (1) Clinically, there are single or multiple lumps in one or both breasts, most of which are accompanied by periodic breast pain, and are often related to emotions and menstrual cycle. The symptoms usually worsen about a week before menstruation, and the lumps and pain are significantly reduced after menstruation, and cannot be relieved on their own for 3 consecutive months.

[0045] (2) Exclude physiological breast pain, such as mild breast tenderness before menstruation, breast pain during puberty, and mastalgia with only breast pain and no lump.

[0046] (3) During clinical examination, one or more irregular nodules of varying sizes can be palpated in the breast. They are firm in texture and mostly located in the upper outer quadrant. The nodules are not adhered to the surrounding tissues, can be moved, and are often slightly tender. The axillary lymph nodes are not large.

[0047] (4) Use auxiliary detection methods such as mammography or plate radiography, B-ultrasound, and thermography. If necessary, perform fine-needle aspiration cytology of the mass and local biopsy pathological examination to rule out other benign and malignant breast diseases such as breast cancer and breast fibroadenoma.

[0048] 2.3.2 Traditional Chinese Medicine Diagnostic Criteria for Imbalance of Chong and Ren Channels

[0049] Based on the "Standards for TCM Differentiation and Classification of Breast Hyperplasia" issued at the Eighth Meeting of the Breast Disease Professional Committee of the Chinese Society of Traditional Chinese Medicine Surgery in 2002, the following TCM diagnostic standards and syndrome scoring standards for breast hyperplasia of the Chong and Ren meridian imbalance type are proposed:

[0050] (1) Scanty and pale menstrual flow, or even amenorrhea;

[0051] (2) Lower back pain and weakness, irritability, fatigue, and dizziness;

[0052] (3) Pale tongue and white coating;

[0053] (4) The pulse is weak or soggy.

[0054] 2.3.3 Observation Indicators

[0055] Table 1. Scoring Criteria for Observation Indicators

[0056]

[0057]

[0058] 2.4 Selection of Subjects

[0059] 2.4.1 Inclusion Criteria

[0060] (1) Meets the diagnostic criteria for mammary hyperplasia;

[0061] (2) Meets the diagnostic criteria for imbalance of the Chong and Ren meridians in Traditional Chinese Medicine;

[0062] (3) Women aged 18 to 55 (inclusive);

[0063] (4) Breast ultrasound BI-RADS rating ≤ 3;

[0064] (5) Voluntarily participate in this clinical trial, provide informed consent and sign the informed consent form.

[0065] 2.4.2 Exclusion Criteria

[0066] (1) Women aged <18 or >55;

[0067] (2) Patients with mastitis, simple breast fibroadenoma, simple breast cyst, hyperprolactinemia, or breast cancer;

[0068] (3) Comorbid serious primary diseases of the heart, lungs, brain, liver, kidneys and hematopoietic system, and mental illness;

[0069] (4) Women whose menstrual period lasts more than 7 days, menopausal women, and women with severely irregular menstrual cycles;

[0070] (5) Pregnant or lactating women, and women of childbearing age who do not wish to take effective measures to prevent pregnancy during the trial and for 3 months after the trial;

[0071] (6) Those who take birth control pills and sex hormone medications;

[0072] (7) History of allergy to any component of the test drug;

[0073] (8) Has a long history of alcoholism or drug abuse;

[0074] (9) Has intellectual or mental disabilities;

[0075] (10) Has participated in other clinical trials within the past 3 months;

[0076] (11) Those who are unwilling to cooperate with the investigation.

[0077] 2.4.3 Case Exclusion Criteria

[0078] Cases already enrolled but meeting one of the following criteria should be excluded:

[0079] (1) Those who were included even though they did not meet the inclusion criteria;

[0080] (2) Those who did not take medication as prescribed, making it impossible to determine efficacy, or whose incomplete data affected the assessment of efficacy or safety. 2.4.4 Subject Dropout and Withdrawal Criteria

[0081] All participants who have completed the informed consent form and passed the screening process have the right to withdraw from the trial at any time. Regardless of when or why they withdraw, if they have not completed the entire clinical trial, they are considered dropouts.

[0082] (1) Researcher's decision to withdraw

[0083] For enrolled participants, researchers may decide to withdraw them from the trial if any of the following situations occur during the study.

[0084] ① Those who terminated the trial due to serious adverse reactions during the trial period.

[0085] ② Assessment of other diseases that occur in the subjects during the trial and affect the efficacy and adverse events.

[0086] ③ The researchers believe that the subject is not suitable to continue receiving the study drug.

[0087] (2) Withdrawal by the subject

[0088] ① The subject withdrew the informed consent form.

[0089] ②Those who have poor treatment results, are unwilling to continue the trial treatment, or whose symptoms have worsened and are unable to complete the trial.

[0090] ③ Adverse events that cannot be tolerated.

[0091] (3) Other reasons

[0092] 2.4.5 Handling of Dropout Cases

[0093] (1) After the subjects fall off the test, the researchers should contact the subjects as much as possible by means of telephone, appointment, follow-up, etc., and ask for the reasons, record the last time of medication, and complete the assessment items that can be completed.

[0094] (2) For subjects who withdraw from or interrupt the study, a final evaluation (treatment end visit) should be completed as much as possible. The evaluation process, results, and description of the reasons for subject withdrawal must be recorded in detail in the original data and case report form.

[0095] 2.4.6 Test Termination Criteria

[0096] (1) The ethics committee, sponsor, or investigator believes that the investigational drug poses a significant safety risk;

[0097] (2) Sponsors may terminate the study for any scientific, medical or ethical reason, but must take into full account the rights, safety and health of the participants in the study.

[0098] (3) Other reasons why the sponsor or researcher deems it inappropriate to continue the trial.

[0099] 2.5 Treatment Plan

[0100] 2.5.1 Specifications of the investigational drug

[0101] Medicine: Chu Feng Jing; Specification: 10 vials per box, 10ml per vial.

[0102] 2.5.2 Packaging of test drugs

[0103] The smallest unit of commercially available packaging (box) should be labeled "For clinical trial use only".

[0104] 2.5.3 Drug Distribution and Storage

[0105] 2.5.3.1 Distribution and Recovery of Investigational Drugs

[0106] After enrollment, the investigational drug administrator (responsible for the storage, distribution, collection, recording, and return or repatriation of the investigational drugs) distributes the medication. The number of boxes distributed per visit is calculated based on menstrual cycles. Any remaining medication is collected during follow-up visits, and the "Drug Distribution and Collection Record Form" is completed promptly based on the subject's medication usage. After the entire trial concludes, the drug administrator is responsible for returning any remaining medication to the sponsoring organization and completing the "Clinical Trial Drug Distribution and Collection Registration Form" for archiving.

[0107] 2.5.3.2 Preservation of test reagents

[0108] The experimental drugs are stored in a dedicated cabinet and managed by the drug administrator, who fills out the "Clinical Trial Drug Storage Record Form".

[0109] 2.5.4 Medication Methods and Course of Treatment

[0110] Usage: Oral administration. 10ml each time, twice a day. Course of treatment: 3 menstrual cycles, continue medication during menstruation.

[0111] 2.5.5 Regulations for Combined Medication Use

[0112] Hormones and traditional Chinese medicines related to this disease are prohibited during the trial. See the list below:

[0113] Table 2 List of Combined Medication Use

[0114]

[0115] 2.5.6 Assessment of Subject Compliance

[0116] During clinical trials, subject compliance mainly involves taking medication as prescribed. Subjects should fully understand the importance of taking medication on time, strictly follow the prescribed medication regimen, and avoid adding other treatments on their own.

[0117] Criteria for determining subject compliance: Investigational drug compliance = (dosage dispensed - unused dosage) / recommended dosage × 100%.

[0118] Patient compliance between 80% and 120% is considered good.

[0119] 2.6 Research Process

[0120] Visit 1: Screening & Enrollment Period (Baseline)

[0121] (1) Obtain written informed consent;

[0122] (2) Obtain demographic data, including the subject's basic characteristics, medical history, past medical history, current other diseases, and treatment information;

[0123] (3) Conduct a physical examination and collect data on vital signs and symptoms;

[0124] (4) Fill in the TCM syndrome scoring table;

[0125] (5) Perform routine blood tests, routine urine tests, urine pregnancy tests, liver function tests (ALT, AST, TBIL, γ-GT, ALP), and kidney function tests (BUN, Cr).

[0126] (6) Breast ultrasound examination to detect the diameter of breast hyperplasia;

[0127] (7) Review the selection / exclusion criteria;

[0128] (8) Dispense the medicine and fill in the "Medicine Dispensing and Recovery Record Form".

[0129] Visit 2: Follow-up period (one menstrual cycle ± 3 days after treatment)

[0130] (1) Count the unused research drugs returned by the subjects and record them in the "Drug Distribution and Recovery Record Form";

[0131] (2) Collect vital signs and symptoms data;

[0132] (3) Fill in the TCM syndrome scoring table;

[0133] (4) Record concomitant medications and adverse events;

[0134] (5) Distribute the next cycle of medication and fill out the "Medication Dispensing and Recovery Record Form".

[0135] Visit 3: Follow-up period (two menstrual cycles ± 3 days after treatment)

[0136] (1) Count the unused research drugs returned by the subjects and record them in the "Drug Distribution and Recovery Record Form";

[0137] (2) Collect vital signs and symptoms data;

[0138] (3) Fill in the TCM syndrome scoring table;

[0139] (4) Record concomitant medications and adverse events;

[0140] (5) Distribute the next cycle of medication and fill out the "Medication Dispensing and Recovery Record Form".

[0141] Visit 4: Follow-up period (3 menstrual cycles ± 3 days after treatment)

[0142] (1) Count the unused research drugs returned by the subjects and record them in the "Drug Distribution and Recovery Record Form";

[0143] (2) Conduct a physical examination and collect data on vital signs and symptoms;

[0144] (3) Fill in the TCM syndrome scoring table;

[0145] (4) Perform routine blood tests, routine urine tests, urine pregnancy tests, liver function tests (ALT, AST, TBIL, γ-GT, ALP), and kidney function tests (BUN, Cr).

[0146] (5) Breast ultrasound examination to detect the diameter of breast hyperplasia;

[0147] (6) Record concomitant medications and adverse events;

[0148] The clinical trial process is shown in Table 3.

[0149] Table 3 Clinical Trial Process

[0150]

[0151]

[0152] Notes: 1. Complete blood count: white blood cells, neutrophils, lymphocytes, red blood cells, hematocrit, hemoglobin, platelets. 2. Urinalysis: urine protein, urine occult blood, urine red blood cells, urine white blood cells, urine specific gravity.

[0153] 2.7 Efficacy Evaluation

[0154] 2.7.1 Observation Indicators

[0155] (1) Demographic data and basic characteristics of the subjects: age, ethnicity, marital status, menstruation and fertility status, etc.

[0156] (2) General clinical data: course of disease, medical history, comorbidities and medications, allergy history.

[0157] (3) Therapeutic efficacy indicators:

[0158] ①Main indicators: breast pain and lump size;

[0159] ② Secondary indicator: Traditional Chinese medicine syndrome;

[0160] ③Comprehensive efficacy indicators: disease efficacy; syndrome efficacy.

[0161] (4) Safety observation indicators: ① Observe adverse events at any time; ② Vital signs (blood pressure, respiration, heart rate); ③ Abnormal changes in various laboratory indicators before and after treatment: blood routine, urine routine, liver function (ALT, AST, TBIL, γ-GT, ALP), kidney function (BUN, Cr), electrocardiogram.

[0162] 2.7.2 Assessment of efficacy and safety

[0163] 2.7.2.1 Determination of primary efficacy indicators

[0164] Appropriate statistical methods were used to perform statistical analysis on breast pain scores and lump size.

[0165] 2.7.2.2 Secondary efficacy indicators

[0166] Traditional Chinese medicine syndromes.

[0167] 2.7.2.3 Comprehensive therapeutic efficacy criteria

[0168] (1) Comprehensive efficacy evaluation criteria for diseases

[0169] Based on the "Diagnostic and Efficacy Evaluation Criteria for Breast Hyperplasia" (Revised Draft) issued by the Surgical Society of the All-China Association of Traditional Chinese Medicine, the specific classification is as follows:

[0170] Cured: The lump disappeared, the breast pain disappeared, and there was no recurrence for 3 months after stopping the medication;

[0171] Significant effect: The maximum diameter of the lump shrinks by more than 1 / 2, and breast pain disappears;

[0172] Effective: ① The maximum diameter of the lump is reduced by less than 1 / 2, and the breast pain is reduced; ② The lump is reduced by more than 1 / 2, but the breast pain is not reduced;

[0173] Ineffective: ① The lump does not shrink, or even grows larger and harder; ② The breast pain is relieved, but the lump does not shrink.

[0174] (2) Traditional Chinese Medicine Syndrome Therapy Evaluation Criteria:

[0175] Syndrome efficacy rate = [(Total score before treatment - Total score after treatment) / Total score before treatment] × 100%

[0176] Cure: The cure rate of symptoms after treatment is ≥90%.

[0177] Significant efficacy: The efficacy rate of symptom relief after treatment is ≥70% and <90%.

[0178] Progress: The efficacy rate of symptom relief after treatment is ≥30% and <70%.

[0179] Ineffective: The efficacy rate of treatment for the symptoms is <30%.

[0180] 2.7.2.4 Safety Evaluation Standards

[0181] Level 1: Safe, no adverse reactions;

[0182] Level 2: Relatively safe. If adverse reactions occur, no treatment is required, and medication can be continued.

[0183] Level 3: There are safety concerns and moderate adverse reactions. After treatment, medication can continue.

[0184] Grade 4: Trial terminated due to severe adverse reaction.

[0185] 2.8 Observation of adverse events

[0186] 2.8.1 Relevant Definitions

[0187] Adverse events: The term "adverse event" encompasses the occurrence or exacerbation of any syndrome, symptom, symptom, or disease that occurs in a subject during clinical study observation and affects the subject's health. This term also includes clinically relevant conditions discovered during laboratory or other diagnostic procedures. Adverse events may include: a new illness; worsening of symptoms or signs of a treatment-associated condition, or worsening of a concomitant disease; the effect of a control drug; events unrelated to participation in the trial; or a combination of one or more factors.

[0188] Serious adverse events are any of the following adverse events that occur at any dose of the investigational drug or at any time during the observation period: resulting in death; immediately life-threatening; requiring hospitalization or prolonged hospitalization; disability; resulting in congenital malformation; having significant medical importance (meaning events that do not immediately endanger life or cause death or require hospitalization, but may harm the patient or require measures to prevent one of the consequences defined above); requiring medical treatment to prevent permanent damage or harm.

[0189] Adverse drug reactions: Harmful and unintended reactions that occur during the normal use of a drug at the prescribed dosage and are causally related to the use of the drug. In clinical trials of a new drug or a new use of a drug, where the therapeutic dosage has not yet been determined, all harmful and unintended reactions causally related to the use of the drug should also be considered adverse drug reactions.

[0190] 2.8.2 Adverse Events

[0191] 2.8.2.1 Recording of adverse events

[0192] During the study, the "Adverse Event Record Form" should be filled out truthfully, recording the time of occurrence, severity, duration, effective measures taken, and outcome of adverse events.

[0193] 2.8.2.2 Severity assessment

[0194] Mild: Usually transient and does not affect normal daily activities.

[0195] Moderate: Quite uncomfortable, can affect normal daily activities.

[0196] Severe: Unable to perform normal daily activities.

[0197] 2.8.2.3 Determining Causality with Drugs

[0198] Researchers should accurately record the time, severity, duration, measures taken, and outcome of adverse events occurring during the medication period, and determine the relationship between the adverse event and the investigational drug. The association between the adverse event and the investigational drug should be assessed using a five-level classification: "definitely related, very likely related, possibly related, questionable, and unlikely to be related." For the first three levels of determination, the adverse reaction rate is calculated by summing all three levels as the numerator and the total number of subjects used to evaluate safety as the denominator, as detailed in Table 4.

[0199] Table 4. Criteria for Determining the Causality of Adverse Reactions

[0200]

[0201] 2.8.2.4 Handling of Adverse Events

[0202] (1) Reporting Methods

[0203] Any adverse events, such as subjective discomfort in patients or abnormal laboratory test results, must be taken seriously, carefully analyzed, and immediate measures taken to protect the safety of the subjects.

[0204] (2) Processing procedure

[0205] Detailed records should be kept in the case report form, including details of its duration, outcome, and disappearance, depending on the circumstances.

[0206] (3) Reporting and handling of serious adverse events

[0207] Any serious adverse event that occurs during the trial must be immediately reported to the principal investigator, the ethics committee, and the sponsoring organization. A "Serious Adverse Event Report Form" must be completed, recording the time of occurrence, severity, duration, measures taken, and outcome of the serious adverse event.

[0208] Management measures: When a patient experiences a serious adverse event, they should withdraw from the clinical trial. The principal investigator of the research unit should take appropriate measures based on the drug and the symptoms that occurred. The researchers should record the date, treatment details, and results in detail on the case report form and sign it.

[0209] (4) Adverse event follow-up

[0210] Adverse events that are not resolved at the end of the trial or when a subject withdraws early must be followed up until any of the following conditions are met:

[0211] Event resolved; event stabilized; event returned to baseline level (if a baseline value is available); event can be attributed to a drug other than the investigational drug or factors unrelated to the study, or when further information is unlikely to be available (patient or healthcare personnel refuse to provide more information, or there is evidence that the patient was lost to follow-up despite best efforts).

[0212] 2.9 Data Management

[0213] 2.9.1 Data Recording and Entry

[0214] The data administrator establishes an Epidata (v3.1) database based on the case report forms for data entry. Database naming must be standardized, easy to read, and easy to search, and its accuracy, security, and confidentiality must be guaranteed. All data is entered independently by two data entry personnel in duplicate. After the data is entered and verified in duplicate, the data administrator formulates the scope and logical checks for the data based on the ranges and interrelationships of the indicators in the case report forms, and writes corresponding computer programs to perform data verification. All questions arising during data verification are promptly communicated to the monitor in the form of a question form, requiring researchers to provide answers.

[0215] After data entry and verification are completed as required, original case report forms can be archived and saved in numerical order, and a retrieval catalog should be filled out for future reference. Electronic data files should be categorized and stored with multiple backups to prevent damage.

[0216] All file transfers are properly recorded and signed, and are stored in accordance with GCP regulations.

[0217] 2.9.2 Managing Data

[0218] 2.9.2.1 Data Locking

[0219] After the data has been reviewed and the established database has been confirmed to be correct, the principal researcher, sponsor, and statistical analysts will lock the data. Once locked, the data files will not be modified. Any issues discovered after data locking will be corrected during the statistical analysis process after confirmation.

[0220] 2.9.2.2 Data Processing

[0221] After all the research data has been entered into the database and locked, and statistical analysis has been completed, the statistical analysts will write a statistical analysis report, which will then be submitted to the principal investigator of this experiment to write a research report.

[0222] 2.9.2.3 Data Encoding

[0223] The Data Center (DM) performs medical coding, including coding adverse events (AEs). Adverse events are coded according to the MedDRA 21.0 dictionary. During the coding process, if any event cannot be coded due to inappropriate, inaccurate, or ambiguous medical terminology, the DM can challenge it to the researchers.

[0224] Before the database is locked, medical experts review the medical codes.

[0225] 2.9.2.4 Data Quality Check

[0226] After the data cleaning is completed, non-project team members within the data management department will check the data quality. Key data (important data determined by the research plan) will be checked 100%, and non-key data will be sampled from a certain range for inspection. A final data quality inspection report will then be generated.

[0227] 2.9.2.5 Data Audit

[0228] After the database cleanup is completed, the data administrator writes a "Data Audit Report" for use in data verification meetings.

[0229] The audit report should focus on recording the following key information: number of enrolled cases, dropout and exclusion cases, deviations from or violations of the protocol, compliance data, concomitant medications, adverse events, and other data related to the evaluation indicators.

[0230] During the data review meeting, the analysis of the review report was discussed and the segmentation of the target population was determined.

[0231] 2.10 Statistical Analysis

[0232] 2.10.1 Analyzing the dataset

[0233] (1) Full Analysis Set (FAS): This refers to an ideal set of subjects that closely approximates the intention-to-treat principle, including all subjects who were randomized, used the study drug at least once, and underwent at least one post-treatment efficacy evaluation. When the primary efficacy endpoint is missing, the LOCF (last observation carry-forward) method is used for estimation. Missing values ​​for comparability analysis and secondary efficacy endpoints are not carried forward; analysis is based on the actual data obtained.

[0234] (2) Protocol Compliance Set (PPS): This refers to the set of subjects who meet the inclusion criteria, do not meet the exclusion criteria, complete the treatment regimen, have good medication adherence, and do not significantly violate the trial protocol. The PPS will be determined by the final data review report.

[0235] The efficacy evaluation of this trial was performed using PPS and FAS analyses.

[0236] (3) Safety set (SS): Subjects who received at least one treatment after randomization and underwent a post-treatment safety assessment. Missing values ​​in the safety set are not carried over. The incidence of adverse reactions is calculated using the number of cases in the safety set as the denominator.

[0237] 2.10.2 Statistical Analysis Plan

[0238] All statistical analyses will be performed using SAS 9.4 statistical analysis software.

[0239] Statistical descriptions: For quantitative variables, list the number of cases, number of missing cases, mean, standard deviation, quartiles, median, minimum, and maximum for each group. For categorical variables, list the number of cases, number of missing cases, frequency, and percentage for each group.

[0240] For quantitative data, before-and-after comparisons are performed using paired t-tests (for normal distributions, the Kolmogorov-Smirnov method is used for normality testing) or Wilcoxon rank-sum tests, depending on the distribution. For categorical data, before-and-after comparisons are performed using the McNemar test or the exact probability method; for ordinal data, the CMH test is used.

[0241] 2.10.3 Statistical Analysis Content

[0242] (1) Study on case completion

[0243] Summarize the enrollment and completion numbers, and determine the three analysis datasets (FAS, PPS, SS); list the enrollment, dropout, exclusion, and completion cases, as well as the number of cases in each analysis dataset; provide a detailed list describing the total dropout rate, reasons for termination, and dropout rate due to adverse events; provide a statistical description of subject compliance, and provide a detailed list describing the details of subjects with poor compliance.

[0244] (2) Baseline and demographic information

[0245] Statistical demographic information, general characteristics of subjects, general clinical data, vital signs, and baseline information of efficacy indicators.

[0246] (3) Evaluation of therapeutic effect

[0247] ①Main efficacy indicators: the rate of change in breast pain and lump size relative to baseline after treatment;

[0248] ② Secondary efficacy indicator: the rate of change of TCM syndrome relative to baseline after treatment;

[0249] ③Comprehensive efficacy indicators: overall efficacy of the disease; efficacy of TCM syndrome differentiation.

[0250] 2.10.4 Safety Evaluation

[0251] Safety evaluation was performed on the SS dataset. Based on the requirements for adverse reaction relevance, the incidence rates of adverse events, adverse reactions, important adverse events, serious adverse events, and serious adverse reactions were calculated. A detailed list was created describing each adverse event, adverse reaction, important adverse event, serious adverse event, and serious adverse reaction, including its name, occurrence time, severity, relationship to the investigational drug, and whether withdrawal was due to the adverse event.

[0252] Calculate the incidence of combined medication use and provide a detailed list of the combined medications, including the name of the medication, dosage, start time, and end time.

[0253] Calculate the changes in laboratory test and electrocardiogram (ECG) results before and after treatment; provide a detailed list of laboratory test and ECG results that were normal before treatment but abnormal after treatment, and vice versa. Calculate the number of cases where laboratory test indicators changed from "normal" to "abnormal" before and after the trial, and the rate of change. Provide a detailed list of laboratory indicators, ECG results, abnormal physical examination cases, and their clinical interpretations.

[0254] 2.11 Clinical Research

[0255] The trial adopted a single - center (the clinical research work plan was completed by Hongjitang Chinese Medicine Hospital), open (open - label trial, without blinding), and single - arm (no control group was set in this trial) clinical research.

[0256] A total of 33 female subjects were included, with 5 aged 20 - 30 years, 12 aged 30 - 40 years, 15 aged 40 - 50 years, and 1 aged 50 - 55 years. The general medication duration was 60 - 90 days, 10 ml each time, twice a day. After treatment, the lump size, menstrual volume, menstrual color, and traditional Chinese medicine symptoms of the 33 patients were significantly improved compared with those before treatment, and the differences were statistically significant (P < 0.05).

[0257] Table 5 Clinical efficacy of 33 patients after treatment

[0258] content Number of examples get well Effective efficient invalid Clinical efficacy 33 4(12.1％) 16(48.5％) 11(33.3％) 2(6.1％)

[0259] Table 6 Comparison of breast pain and lump size of 33 patients before and after treatment

[0260] content Number of examples Before treatment After treatment Z P Breast pain 33 4.55±1.44 3.03±1.67 -3.784 ＜0.05 lump size 33 4.12±1.49 2.61±1.46 -3.646 ＜0.05

[0261] Table 7 Comparison of traditional Chinese medicine symptom scores of 33 patients before and after treatment

[0262] content Number of examples Before treatment After treatment T P Total score of TCM syndrome 33 19.22±3.66 10.39±5.34 9.465 ＜0.05

[0263] The trial results showed that the total effective rate of Chufengjing in treating mammary gland hyperplasia was 93.9%. At the same time, it could effectively relieve the lump hardness, pain, and tenderness, improve the texture of the mammary gland, and had a good effect on anti - mammary gland hyperplasia. By analyzing the traditional Chinese medicine syndrome score table, after treatment with Chufengjing, the menstrual volume and menstrual color were significantly improved, and the differences were statistically significant (P < 0.05); after treatment, the total scores of symptoms such as soreness and weakness in the waist, fatigue, irritability, dizziness, etc. were significantly improved compared with those before treatment, and the differences were statistically significant. It shows that Chufengjing can effectively improve mammary gland hyperplasia of the type of disharmony between thoroughfare and conception vessels.

[0264] There were no adverse reactions during the trial.

[0265] As described above, these are only the embodiments of the present application. The protection scope of the present application is not limited by these specific embodiments, but is determined by the claims of the present application. For those skilled in the art, various changes and modifications can be made to the present application. Any modification, equivalent replacement, improvement, etc. made within the technical idea and principle of the present application shall be included within the protection scope of the present application.

Claims

1. The use of Jufengjing in the preparation of a drug for treating breast hyperplasia, characterized in that, The breast hyperplasia described is a type of breast hyperplasia caused by imbalance of the Chong and Ren meridians; the "Chicken Phoenix Essence" is made from the following ingredients in parts by weight: 6g Amomum villosum, 5g Cinnamomum cassia, 4g Paeonia suffruticosa, 5g Acorus tatarinowii, 7g Aquilaria sinensis, 8g Astragalus membranaceus, 6g Glycyrrhiza uralensis, 4g Panax ginseng, 3g Deer antler, 9g Paeonia lactiflora, 8g Psoralea corylifolia, 9g Rubus idaeus, 5g Nelumbo nucifera stamens, 8g Lycium barbarum, 14g Alisma plantago-aquatica, 18g Rehmannia glutinosa, 11g Cistanche deserticola, 15g Dioscorea opposita, 6g Angelica sinensis, 5g Achyranthes bidentata, 8g Poria cocos, 5g Epimedium brevicornu, 7g Cynomorium songaricum, 12g Cibotium barometz, 5g Eucommia ulmoides, 75g sheep testicles, 12g sheep penis, and 150g chicken fetus.

2. The application according to claim 1, characterized in that, The Chu Feng Jing is a pure traditional Chinese medicine oral preparation; the dosage form is oral liquid, powder, granules, pills, tablets or capsules.

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