Pharmaceutical composition for treating benign prostatic hyperplasia and preparation thereof

Abstract

The invention relates to a pharmaceutical composition for treating benign prostatic hyperplasia and a preparation thereof, and is characterized in that the pharmaceutical composition is prepared from the following raw material medicines in parts by weight: 4.0-4.7 parts of astragalus membranaceus, 3.0-3.8 parts of periplaneta americana, 2-3 parts of radix aconiti carmichaeli, 2-3 parts of ground beetle, 1.4-1.9 parts of turmeric and 0.37-0.95 part of liquorice, and the raw material medicines are prepared into powder or pills. The pharmaceutical composition and the preparation thereof have the advantages of improvement of lower urinary tract symptoms caused by benign prostatic hyperplasia, fast effect taking, short-term reduction of the volume of hyperplasia prostate, small dosage and low cost.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition and formulation for treating benign prostatic hyperplasia, belonging to the field of pharmaceutical technology. Background Technology

[0002] Benign prostatic hyperplasia (BPH) has an extremely high prevalence, making it one of the most common urinary system diseases affecting middle-aged and elderly men. The prevalence is approximately 20% in men aged 40-49, rises sharply to about 40-50% in those aged 50-59, reaches 60-70% in those aged 60-69, and exceeds 80% in those over 70, with some studies showing it can reach over 90% in those over 80. With the accelerating aging of the global population, the number of BPH patients continues to grow rapidly. In China, based on its large population and rapid aging, it is estimated that there are over 100 million BPH patients, and the number is still increasing.

[0003] BPH significantly impacts quality of life: it primarily causes lower urinary tract symptoms (LUTS), including storage symptoms such as urinary frequency, urgency, and urge incontinence; voiding symptoms such as hesitancy, weak stream, straining, post-void dribbling, and prolonged voiding time; and post-voiding symptoms such as a feeling of incomplete bladder emptying. These symptoms severely affect patients' sleep quality, daily activities, social life, mental health, and overall quality of life.

[0004] There are many treatments available for BPH, each with its own advantages and disadvantages.

[0005] Chemical therapy: 5-α reductase inhibitors and α-receptor blockers are currently the first-line drugs for the treatment of BPH.

[0006] 5-α reductase inhibitors work by reducing prostate volume, improving symptoms, and potentially reducing the need for surgery. However, they have drawbacks such as slow onset of action and poor safety profile. For example, finasteride, in a randomized, double-blind, controlled clinical trial involving 3040 patients followed for 48 months, demonstrated that finasteride could reduce prostate volume by 18%, with statistically significant improvement in symptoms observed from the 8th month. After one year of treatment, prostate volume no longer decreased significantly. However, major adverse reactions included decreased libido, erectile dysfunction, and reduced ejaculate volume. Other adverse reactions included ejaculatory dysfunction, rash, breast enlargement, or tenderness.

[0007] Alpha-receptor blockers include non-selective alpha-receptor blockers (such as phenoxybenzamine), selective alpha-1 receptor blockers (such as alfuzosin, doxazosin, and terazosin), and superselective alpha-1 receptor blockers (such as tamsulosin). Class 1 drugs are rarely used to treat BPH due to their significant side effects, while the latter two classes are more commonly used. Alpha-receptor blockers can only improve the symptoms of benign prostatic hyperplasia (BPH) and cannot reduce prostate volume. Regarding the efficacy of tamsulosin, the Cochrane systematic review synthesized 13 randomized controlled trials (tamsulosin compared to placebo or other treatments, with treatment duration of at least 4 weeks), including 3418 BPH patients (45-85 years old, mean 64 years; mean Boyarsky symptom score of 10.2, mean IPSS score of 19.5, and mean maximum urinary flow rate of 9.9 ml / s before treatment), followed up for 4-26 weeks. As a result, tamsulosin improved symptoms by 20%-48% and increased maximum urinary flow rate by 1.2-4.0 ml / s (13%-44%); while the mean changes in the placebo group were 18%-28%. Tamsulosin was significantly more effective than placebo. The main side effects were dizziness and abnormal ejaculation.

[0008] Surgical treatment: The efficacy is definite, but because the patients are older and have weaker physical functions and resistance, although surgery is the most effective way to treat benign prostatic hyperplasia, surgery is prone to cause varying degrees of damage to patients. At the same time, the surgery is expensive, has high risks, and there is still a possibility of recurrence after surgery.

[0009] Interventional therapy: It is minimally invasive and has good efficacy, but its clinical application is limited by the limitations of technology and equipment and the high medical costs.

[0010] Traditional Chinese medicine (TCM) treatment has unique characteristics and advantages in the treatment of BPH. It combines disease identification and syndrome differentiation, offers diverse treatment methods, has relatively few side effects, and enjoys high patient acceptance. However, its drawbacks include a slower onset of action, a longer treatment period, and the ability to effectively improve lower urinary tract symptoms such as urinary frequency, urgency, weak urine stream, difficulty urinating, and incomplete urination. There are no reports of TCM alone reducing prostate volume, and the dosage is usually large, resulting in high costs.

[0011] Therefore, there is an urgent need for traditional Chinese medicine compositions that can quickly control lower urinary tract symptoms, effectively reduce glandular volume, and are available in small doses and at low cost. Summary of the Invention

[0012] The purpose of this invention is to provide a pharmaceutical composition and its formulation that can rapidly improve lower urinary tract symptoms caused by benign prostatic hyperplasia, reduce the volume of the enlarged prostate in a short period of time, has good safety, and requires a small dosage and is inexpensive.

[0013] The objective of this invention is achieved through the following technical solution: A pharmaceutical composition and preparation thereof for treating benign prostatic hyperplasia, characterized in that it is composed of the following raw materials: Astragalus membranaceus 4.0-4.7 parts, American cockroach 3.0-3.8 parts, Aconitum carmichaelii 2-3 parts, Eupolyphaga sinensis 2-3 parts, Curcuma longa 1.4-1.9 parts, and Glycyrrhiza uralensis 0.37-0.95 parts.

[0014] The above-mentioned pharmaceutical composition and preparation for treating benign prostatic hyperplasia are characterized in that: preferably composed of the following raw materials: Astragalus membranaceus 4.5 parts, American cockroach 3.6 parts, Aconitum carmichaelii 2.5 parts, Eupolyphaga sinensis 2.5 parts, Curcuma longa 1.5 parts, and Glycyrrhiza uralensis 0.4 parts.

[0015] The above-mentioned pharmaceutical composition for treating benign prostatic hyperplasia is characterized in that it is prepared as a powder or pill.

[0016] The above-mentioned pharmaceutical composition and preparation for treating benign prostatic hyperplasia are characterized in that: a pill form is preferred.

[0017] This completes the invention.

[0018] The dosage of this drug combination for treating benign prostatic hyperplasia is 5g three times a day, with one month constituting one course of treatment.

[0019] The above-mentioned raw material composition is in grams, which is the daily dosage for patients. Large-scale production can use kilograms or tons as the weight unit, but the daily dosage for patients remains unchanged.

[0020] Benign prostatic hyperplasia (BPH) falls under the category of "urinary retention" in Traditional Chinese Medicine (TCM), often related to kidney qi deficiency leading to blood stasis, kidney qi deficiency causing weak bladder qi transformation, and blood stasis obstructing the meridians. In this formula, Astragalus membranaceus (Huangqi) is the principal ingredient, greatly tonifying the spleen and stomach qi, replenishing kidney qi, assisting qi transformation to promote water metabolism, raising yang and lifting prolapse, promoting fluid circulation, and relieving urinary weakness. American cockroach (Periplaneta americana) and ground beetle (Eupolyphaga sinensis) are the assistant ingredients, invigorating blood circulation, dispersing blood stasis, promoting diuresis and reducing swelling, breaking up accumulations and clearing the meridians; their combination with Astragalus membranaceus ensures "tonification without stagnation." Aconitum carmichaelii (Fuzi) and Curcuma longa (Zihuang) are the adjuvant ingredients. Aconitum carmichaelii warms kidney yang and assists qi transformation, resolving urinary obstruction caused by deficiency and cold in the lower jiao; its combination with Astragalus membranaceus achieves the effect of "tonifying qi and warming yang." Curcuma longa invigorates blood circulation, promotes qi flow, clears the meridians and relieves pain, assists ground beetle in dispersing blood stasis, and also guides the medicine to the lower jiao. Licorice root (Gancao) is the guiding ingredient, harmonizing the other ingredients and mitigating the harshness of American cockroach and ground beetle. The combination of these herbs, employing both tonifying and purging methods, addresses both the root cause and symptoms, achieving the effects of invigorating qi and tonifying the kidneys, resolving blood stasis and dissipating nodules.

[0021] This invention treats benign prostatic hyperplasia (BPH) of the kidney deficiency and blood stasis type, exhibiting significant advantages and advancements compared to existing technologies. Its onset of action surpasses that of Western medicine, significantly improving lower urinary tract symptoms within 7-15 days, approaching the onset time of alpha-receptor blockers (such as tamsulosin), without their side effects. A reduction in prostate volume within one month is a significant improvement; currently, the only Western medicine capable of shrinking the prostate, such as finasteride (a 5α-reductase inhibitor), requires continuous use for more than 6 months to achieve this. The dosage is small, only 5g of traditional Chinese medicine decoction pieces per dose, resulting in low treatment costs. It also demonstrates good safety; no safety issues have been found in animal experiments and clinical studies.

[0022] The dosage form of the formulation of this invention was selected through clinical trials. Clinical trials found that using the dosage of the pharmaceutical composition of this invention to prepare decoctions, granules, or oral liquids was clinically ineffective, and even at 10 times the prescription dosage of this invention, the efficacy was not significantly different from that of this invention. Therefore, the formulation of this invention is selected as either powder or pill, with pills being preferred due to the unpleasant odor of powdered medicines.

[0023] The following experimental examples further illustrate the beneficial effects of the present invention.

[0024] I. Clinical Studies of the Pharmaceutical Compositions of the Invention (a) Preparation of drugs for clinical research (water pills of the present invention) Weigh the raw materials: Astragalus membranaceus 22.5kg, American cockroach 18kg, Aconitum carmichaelii 12.5kg, Eupolyphaga sinensis 12.5kg, Curcuma longa 7.5kg, Glycyrrhiza uralensis 2kg.

[0025] The above 6 ingredients are pulverized, passed through an 80-mesh sieve, and mixed evenly. Using purified water as a binder, they are mixed in a mixer until they form a soft material that can be formed into a ball when squeezed but crumbles when lightly pressed. The soft material is then made into water pills with a diameter of about 3mm using a rotary pelleting machine. The pills are dried below 60℃ and polished by rolling in a water chestnut-shaped sugar coating pan to obtain water pills with a smooth surface.

[0026] It was repackaged into 5g sachets, and 15,000 sachets were made for use as experimental drugs.

[0027] Clinical study of the pharmaceutical composition of the present invention for the treatment of benign prostatic hyperplasia 1. Experimental Objective The clinical efficacy and safety of the water pills of this invention in treating benign prostatic hyperplasia were observed.

[0028] 2. Efficacy evaluation indicators 2.1. Changes in clinical symptom scores (IPSS score) after 60 days of treatment; 2.2. Changes in quality of life index score after 60 days of treatment; 2.3. Changes in maximum urinary flow rate (Qmax) and residual urine volume after 60 days of treatment; 2.4. Change in prostate volume after 60 days of treatment (B-ultrasound) (the change is calculated as 0.52 * anteroposterior diameter * left and right diameter * superior and inferior diameter); 2.5. Change in TCM syndrome score after 60 days of treatment.

[0029] 3. Trial design This trial intends to adopt a single-arm before-and-after control trial design.

[0030] 4. Trial population All cases were from the outpatient department of Traditional Chinese Medicine of Ningjin County People's Hospital from August 2023 to February 2024, and the ethics approval number was 2023 Ethics Review No. (006). A total of 60 patients with benign prostatic hyperplasia were included.

[0031] 4.1. Diagnostic criteria 4.1.1. Western medicine diagnostic criteria for benign prostatic hyperplasia The Western medicine diagnostic criteria refer to the "Integrated Traditional Chinese and Western Medicine Multidisciplinary Diagnosis and Treatment Guidelines for Benign Prostatic Hyperplasia" (2022 Edition) edited by Guo Jun, Sun Zixue, etc. and proposed by the Andrology Branch of the Chinese Association of Chinese Medicine Information in 2022.

[0032] 4.1.1.1. Clinical manifestations: The clinical symptoms are mainly LUTS, including storage-phase symptoms, voiding-phase symptoms, and post-voiding symptoms: ① Storage-phase symptoms include frequent urination, urgency, urinary incontinence, and nocturia; ② Voiding-phase symptoms include hesitant urination, difficult urination, and interrupted urination; ③ Post-voiding symptoms include a sense of incomplete urination and dribbling after urination.

[0033] 4.1.1.2. Inquiry, assessment, and physical examination ① For male patients over 50 years old who come to the doctor with LUTS as the main complaint, the possibility of BPH should be considered first. Through detailed inquiry of the medical history for initial assessment and combined with auxiliary examinations to clarify the diagnosis. Use the symptom scoring questionnaire to quantify LUTS and determine the main symptoms, IPSS score (mild symptoms 0 - 7 points, moderate symptoms 8 - 19 points, severe symptoms 20 - 35 points); ② Digital rectal examination: It is one of the important examination items for BPH patients. In most patients, an enlarged prostate can be felt, with a smooth surface, firm, elastic texture, clear edges, and the middle groove becoming shallow or disappearing.

[0034] 4.1.1.3. Auxiliary examinations ① CT, MRI: Directly observe the prostate to exclude diseases such as urinary system stones and prostate cancer; ② Ultrasound examination: It is carried out through the abdominal wall or rectal approach. Prostate volume > 18 cm 3The residual urine volume in the bladder after urination is >10ml. (Prostate volume calculation method: left-right diameter × anteroposterior diameter × superior-inferior diameter × 0.52); ③ Uroflowmetry test: For men over 50 years old, a Qmax ≥ 15 ml / s is considered normal. A Qmax of 15-10 ml / s may indicate obstruction, while a Qmax < 10 ml / s definitely indicates obstruction. ④ Serum prostate-specific antigen (PSA) measurement: This is significant for ruling out prostate cancer; a level <4 ng / ml can rule out the possibility of prostate cancer.

[0035] 4.1.2. Traditional Chinese Medicine Diagnostic Criteria for Urinary Retention, an Indication of this Invention 4.1.2.1. The diagnostic criteria for "urinary retention" in Traditional Chinese Medicine include: 4.1.2.1.1. Difficulty urinating, dribbling, or complete urinary retention, without urethral pain, and lower abdominal distension; 4.1.2.1.2. More common in elderly men; 4.1.2.1.3. Digital rectal examination in men may reveal benign prostatic hyperplasia or obvious dullness on percussion of the bladder area; 4.1.2.2. Referring to the "Guidelines for the Multidisciplinary Diagnosis and Treatment of Benign Prostatic Hyperplasia with Integrated Traditional Chinese and Western Medicine" (2022 Edition) edited by Guo Jun, Sun Zixue, et al., and proposed by the Andrology Branch of the China Association of Traditional Chinese Medicine Information, a diagnosis is established if the patient presents with one primary symptom, two secondary symptoms, and tongue and pulse examination. Quantitative diagnosis is used in clinical research: based on the principle of 2 points for each primary symptom and 1 point for each secondary symptom or tongue and pulse examination, a cumulative score ≥5 indicates a valid diagnosis.

[0036] Kidney deficiency and blood stasis syndrome: Main symptoms: difficulty or frequency of urination, especially nocturia; clear urine; weak flow; shortened range; or involuntary leakage of urine that cannot be controlled. Secondary symptoms: pale complexion, weak spirit, aversion to cold, cold and soreness in the lower back and knees; Tongue and pulse: The tongue is dark red, or has petechiae or ecchymosis, with a white coating, and the pulse is deep, thready, and hesitant.

[0037] 4.2. Inclusion Criteria 4.2.1. Meets the diagnostic criteria for benign prostatic hyperplasia in Western medicine; 4.2.2. Meets the diagnostic criteria for kidney deficiency and blood stasis syndrome in Traditional Chinese Medicine; 4.2.3. International Prostate Symptom Score (IPSS) ≥8 points and <20 points; 4.2.4. Individuals with a maximum urinary flow rate <15 ml / s; 4.2.5. Those with a prostate volume ≥18cm³; 4.2.6. Males aged 50 to 80 (inclusive); 4.2.7. Voluntarily participate in clinical trials and sign informed consent forms.

[0038] 4.3. Exclusion Criteria 4.3.1. Any condition other than benign prostatic hyperplasia that the researcher determines may cause urinary symptoms or changes in urinary flow rate (e.g., neurogenic bladder, bladder neck fibrosis, bladder neoplasms, bladder tumors, urinary tract stones, urethral stricture, phimosis or penile tumors, acute or chronic prostatitis, prostate cancer, acute or chronic urinary tract infections, acute or chronic renal failure, etc.). 4.3.2. Patients requiring minimally invasive prostate surgery or other surgical treatment; 4.3.3. Those with a history of pelvic trauma or pelvic surgery; 4.3.4. Patients with a history of prostate surgical treatment: including transurethral resection of the prostate (TURP), transurethral enucleation of the prostate (TUEP), laser, transrectal high-intensity focused ultrasound (HIFU), transurethral needle ablation (TUNA), balloon dilation, stent replacement, or other invasive procedures for treating BPH; 4.3.5. Individuals with serum PSA > 4 ng / mL; 4.3.6. Individuals with residual urine volume > 100 ml or those deemed necessary for catheterization by the researcher; 4.3.7. Patients with serious primary diseases and functional disorders of the heart, brain, liver, kidneys, hematopoietic system, endocrine system, etc.; those with ALT or AST values ​​> 1.5 times the upper limit of normal or Cr values ​​> the upper limit of normal; and those with congenital malformations of the reproductive system. 4.3.8. Patients with unstable blood glucose control in diabetes, with glycated hemoglobin ≥8%, or those with diabetic nephropathy requiring medication control; 4.3.9. Long-term use of drugs that affect bladder function (such as anticholinergic drugs, drugs that affect mental and emotional state, etc.); 4.3.10. Those who have used Chinese or Western medicines for the treatment of benign prostatic hyperplasia (such as alpha-receptor blockers, 5α-reductase inhibitors, and M-receptor antagonists) within 2 weeks prior to participating in the trial; 4.3.11. Individuals with a history of alcoholism, drug abuse, or mental illness; 4.3.12. Patients with allergic constitutions or allergies to the test drug or its components; 4.3.13. Patients who have participated in other clinical trials within the past 3 months; 4.3.14. Subjects or their spouses who plan to conceive during the trial period and within 6 months after discontinuation of medication; 4.3.15. Other patients deemed unsuitable for participation in this clinical study by the researchers.

[0039] 5. Clinical trials 5.1. Dosage and Administration The water pills of this invention are taken with warm water after meals, one packet (equivalent to 5g of medicinal slices) at a time, three times a day.

[0040] 5.2. Dosing cycle 60 days.

[0041] 5.3. Drug packaging, inventory, and compliance assessment 5.3.1. Packaging and Labeling Each package must be labeled with the words "For clinical research use only". The label should also include the trial protocol number, drug number, drug name, indications, specifications, dosage and administration, storage method, expiration date, and manufacturer.

[0042] 5.3.2. Inventory of medications used in the study During each follow-up visit, the observing physician should take stock of the patient's remaining medications, inquire whether the patient has taken the medications on time and in the correct dosage, and note any instances of loss, missed doses, or under-dosing. This information should be promptly recorded in the research medical record for use in assessing clinical medication adherence.

[0043] 5.3.3. Assessment of Subject Compliance In clinical research, 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.

[0044] Medication adherence in subjects was assessed using the drug counting method, combined with questioning when necessary. Medication adherence in the study = (Total amount of prescribed medication taken / Total amount of prescribed medication to be taken) × 100% Note: The total amount of medication to be taken according to the treatment endpoint should be calculated.

[0045] 5.4. Combined medication and treatment 5.4.1. During the study, the use of other Chinese or Western medicines that have therapeutic effects on benign prostatic hyperplasia or have similar functions and indications to the test drug, or treatment methods such as acupuncture, moxibustion, and acupoint application are prohibited.

[0046] 5.4.2. For medications or other treatments that must be continued due to other co-existing conditions, the name of the medication (or other treatment), dosage, frequency of use, and time of administration must be recorded.

[0047] 6. Exit criteria for cases 6.1. Researcher's decision to withdraw criteria 6.1.1. If an allergic reaction or serious adverse event occurs, the study should be stopped according to the doctor's judgment; 6.1.2. Patients who contracted other diseases during the study, affecting the assessment of efficacy and safety; 6.1.3. Subjects with poor compliance (<80%, or >120%), or who voluntarily change medications midway or add Chinese or Western medicines prohibited by this regimen; 6.1.4. Individuals who seriously violate inclusion or exclusion criteria and should not have been included in the study.

[0048] 6.2. Criteria for Subject Voluntary Withdrawal (Disengagement) 6.2.1. The study is terminated if, for any reason, the patient is unwilling or unable to continue the clinical study and requests to withdraw from the study by the attending physician; 6.2.2. Subjects who, although not explicitly withdrawing from the study, ceased receiving medication and testing and were thus lost to follow-up.

[0049] 6.3. Regulations for Terminating All Clinical Studies The completion of the follow-up of the last case in the plan marks the end of a clinical study.

[0050] 7. Observe the content and timeliness. 7.1. General information on subject enrollment 7.1.1. Demographic information and height and weight Demographic information includes age, sex, ethnicity, and source of infection. Height and weight are measured.

[0051] 7.1.2. Medical History The medical history should include the present illness, past medical history, allergy history, and any comorbidities.

[0052] The present medical history should include the chief complaint, the onset of the disease, its course, and the diagnosis, treatment, and outcomes since its onset. Additionally, any other diseases or accompanying injuries the subject currently has besides benign prostatic hyperplasia (BPH), i.e., underlying diseases, should be recorded, including the diagnosis or name of the injury and its treatment.

[0053] Past medical history should include information on diseases that have affected the function of vital organs, as well as other medical history and treatments that researchers deem clinically significant (including but not limited to mental illnesses).

[0054] Allergy history should include food allergy history and drug allergy history.

[0055] 7.2. Safety Observation Indicators 7.2.1. Vital signs and physical examination Body temperature, respiration, heart rate, and blood pressure.

[0056] 7.2.2. Biological Specimen Collection and Laboratory Assessment This study requires the collection of blood and urine samples for laboratory tests such as complete blood count, blood biochemistry, and urinalysis to assess the safety of the investigational drug.

[0057] Complete blood count (WBC, RBC, NEUT%, LYMPR%, HB, PLT), urinalysis (PRO, LEU, ERY), liver function tests (ALT, AST, TBIL, γ-GT), kidney function tests (UREA or BUN, Cr), coagulation panel (TT, PT, APTT, FIB), 12-lead electrocardiogram.

[0058] 8. Evaluation of therapeutic effect 8.1. Changes in clinical symptom scores (IPSS score) after 60 days of treatment; 8.2. Changes in quality of life index score after 60 days of treatment; 8.3. Changes in maximum urinary flow rate (Qmax) and residual urine volume after 60 days of treatment; 8.4. Changes in prostate volume (B-ultrasound) 60 days after treatment (calculated as anteroposterior diameter × lateral diameter × superior-inferior diameter × 0.52); 8.5. Changes in TCM syndrome scores after 60 days of treatment.

[0059] ① Clinically cured: TCM clinical symptoms and signs disappear or basically disappear, and the syndrome score decreases by ≥95%.

[0060] ② Significant improvement in TCM clinical symptoms and signs, with a reduction in syndrome score of ≥60%.

[0061] ③ Effective TCM clinical symptoms and signs have improved, and the syndrome score has decreased by ≥30%.

[0062] ④ Ineffective TCM clinical symptoms and signs showed no significant improvement or even worsened, with the syndrome score decreasing by less than 30%.

[0063] Note: The calculation formula (nimodipine method) is: [(pre-treatment score - post-treatment score) / pre-treatment score] × 100%.

[0064] According to the "Standards for Grading and Scoring Symptoms, Signs and Auxiliary Examinations" and the "Standards for Evaluating Treatment Efficacy", if any two of the following criteria are met, such as IPSS, residual urine volume in the bladder, and prostate volume, the treatment is considered to be effective.

[0065] 9. Safety Evaluation Laboratory test indicators, adverse event rate, and adverse reaction rate. The analysis primarily focuses on laboratory test indicators that showed changes from positive to negative, or worsened from abnormal to positive.

[0066] 10. Quality Control Sponsors and investigators should employ standard operating procedures to ensure quality control and the implementation of quality assurance systems in clinical trials. All observations and findings in clinical trials should be verified to ensure data reliability and that all conclusions are derived from raw data. Quality control must be implemented at every stage of data processing to ensure all data are reliable and processed correctly.

[0067] 11. Data Management The data manager develops a data management plan based on GCP principles and clinical trial details (such as protocols, e-CRFs, and project realities). This plan documents, describes, and defines all aspects of data management, guiding the entire data management process.

[0068] 12. Statistical Analysis Clinically collected data were analyzed using SPSS 27.0 software. Measurement indicators were described using mean and standard deviation. Analysis was performed before and after treatment. For measurement data conforming to a normal distribution, a t-test was used; for those not conforming to a normal distribution, a Wilcoxon rank-sum test was used. Hypothesis testing was uniformly performed using two-tailed tests. Test statistics and their corresponding p-values ​​are provided, with a significance level of 0.05.

[0069] 13. Results 13.1. Analysis of the Subject Population A total of 60 subjects with benign prostatic hyperplasia were enrolled in this trial, and 60 were eventually discharged. The oldest participant was 79 years old, the youngest was 50 years old, and the mean age was (64.18±8.57) years, all of whom met the inclusion criteria.

[0070] No participants violated the protocol in this trial, and compliance was good.

[0071] 13.2. Evaluation of therapeutic effect 13.2.1. Therapeutic Effect Analysis 13.2.1.1. IPSS Scoring Analysis The International Prostate Symptom Scale (IPSS) is currently the internationally recognized authoritative standard for assessing the severity of lower urinary tract symptoms in patients with benign prostatic hyperplasia (BPH). This scale quantifies the severity of lower urinary tract symptoms, providing a basis for clinical diagnosis and treatment evaluation. The IPSS scale quantifies patients' subjective feelings through seven voiding symptom questions, including incomplete bladder emptying, intermittent urination, and weak urine stream. Each item is scored from 0 to 5 points based on symptom frequency (asymptomatic to almost always), with a total score of 0 to 35 points. Based on the total score, symptom severity is divided into three levels: 0-7 points for mild symptoms, 8-19 points for moderate symptoms, and 20-35 points for severe symptoms.

[0072] An analysis of IPSS scores in 60 patients showed that after two months of treatment, the total IPSS score decreased by 2.46 points from baseline in the first month (a decrease of 16%) and by 5.15 points from baseline in the second month (a decrease of 33%), both statistically significant (P<0.01). After two months of treatment, there were statistically significant differences in urinary incontinence, intervals between urinations less than 2 hours, intermittent urination, weak urine stream, straining to urinate, and nocturia frequency before and after treatment (P<0.05). Among these, the differences in intervals between urinations less than 2 hours, intermittent urination, weak urine stream, straining to urinate, and nocturia frequency before and after treatment were extremely significant (P<0.01). See Tables 1 and 2 for details. Note: * indicates statistically significant difference; ** indicates extremely significant difference.

[0073] Table 1 - Changes in IPSS score from baseline one month after treatment

[0074] Table 2 - Changes in IPSS score from baseline after two months of treatment

[0075] 13.2.1.2. Quality of Life Score Analysis The Quality of Life (QoL) score quantifies a patient's subjective level of distress using a single question ("How do you feel about your quality of life if your symptoms persist?"). The score ranges from 0 to 6 (0 indicates no impact, and 6 indicates extreme distress). It overcomes the limitations of the IPSS, which only focuses on symptom frequency, and provides a more comprehensive reflection of the disease's impact on a patient's psychological, social, and work abilities.

[0076] An analysis of the quality of life scores of 60 patients showed that after two months of treatment, the total quality of life score decreased by 0.97 points from baseline in the first month (lower scores indicate higher quality of life), a decrease of 25%, which was statistically significant (P<0.01). In the second month, the total quality of life score decreased by 1.42 points from baseline, a decrease of 36%, also statistically significant (P<0.01). This indicates that the water pills of the present invention have a significant effect on improving patients' quality of life. See Tables 3 and 4 for details. Note: * indicates statistically significant difference; ** indicates highly significant statistical difference.

[0077] Table 3 - Changes in quality of life scores from baseline one month after treatment

[0078] Table 4 - Changes in quality of life scores from baseline two months after treatment

[0079] 13.2.1.3. Analysis of Traditional Chinese Medicine Syndrome Scores Traditional Chinese Medicine (TCM) syndrome scoring criteria: Symptoms are categorized into four levels based on severity: none, mild, moderate, and severe. Primary symptoms (frequent urination, difficulty urinating, post-void dribbling) are assigned 0, 2, 4, and 6 points respectively, while secondary symptoms (chest and rib pain, etc.) are assigned 0, 1, 2, and 3 points respectively. Symptom scores and total scores before and after treatment are recorded and compared. The efficacy of TCM syndrome scoring is then evaluated.

[0080] An analysis of TCM syndrome scores in 60 patients showed that after two months of treatment, the total TCM syndrome score decreased by 2.47 points from baseline in the first month (a 15% decrease, statistically significant, P<0.01), and by 5.95 points from baseline in the second month (a 35% decrease, also statistically significant, P<0.01). After two months of treatment, there were statistically significant differences in urinary frequency, dysuria, post-void dribbling, lower abdominal distension, perineal discomfort, scrotal pain, urethral pain, lower back and knee weakness, and fatigue before and after treatment (P<0.05). Among these, the differences in urinary frequency, dysuria, post-void dribbling, lower abdominal distension, perineal discomfort, scrotal pain, urethral pain, and fatigue before and after treatment were extremely significant (P<0.01). See Tables 5 and 6 for details. Note: * indicates statistically significant difference; ** indicates extremely significant difference.

[0081] Table 5 - Changes in TCM syndrome scores from baseline one month after treatment

[0082] Table 6 - Changes in TCM syndrome scores from baseline after two months of treatment

[0083] 13.2.1.4. Prostate volume analysis The core pathological problem of benign prostatic hyperplasia (BPH) in middle-aged and elderly men is the enlargement of the prostate gland, which compresses the urethra (especially the prostatic urethra) or bladder neck from three dimensions: anterior / posterior, lateral / lateral, and superior / inferior. This leads to lower urinary tract symptoms (such as difficulty urinating, weak urine stream, urinary frequency, urgency, and incomplete emptying). Reduction in the diameter of the prostate gland relieves compression in different directions, and each has a different emphasis on symptom improvement, as detailed below: The significance of reducing the anteroposterior diameter: It directly reduces the anteroposterior pressure on the urethra, restores the urethral lumen to a near-circular natural shape, and reduces mechanical resistance during urination. The most direct improvement for patients is "smoother urination," where urine can be expelled without straining, and the thickness and range of the urine stream are significantly restored.

[0084] The significance of reducing the lateral diameter: It relieves the lateral pressure on the urethra and restores the lateral space of the urethra. On the one hand, it makes the urine stream more concentrated and without deviation. On the other hand, it reduces the traction or pressure on the urethral sphincter and improves the sphincter's urinary control function. Patients can clearly feel that "the urgency to urinate is reduced" and "there is no residual feeling of pressure after urination". The residual urine volume in the urethra (the amount of urine remaining in the bladder after urination) will decrease accordingly.

[0085] The significance of reducing the vertical diameter: It relieves the vertical pressure on the bladder neck, restores the normal anatomical position and opening of the bladder neck, and allows patients to urinate "faster" (without having to wait for a long time). The bladder can be emptied more completely, and the residual urine volume is significantly reduced, thereby reducing urinary frequency (reduced number of urinations during the day) and nocturia (reduced number of times you get up at night), and alleviating the long-term "overloaded" state of the bladder.

[0086] An analysis of prostate volume in 60 patients showed that after two months of treatment, the total prostate volume decreased by 3.41 cm from baseline in the first month. 3 The decrease rate was 10%; the total prostate volume decreased by 4.04 cm from baseline in the second month. 3 The decrease was 12%. The transverse diameter, longitudinal diameter, and anteroposterior diameter all decreased significantly, with statistically significant differences before and after treatment (P<0.01). See Tables 7 and 8 for details. Note: * indicates statistically significant difference; ** indicates extremely significant statistical difference.

[0087] Table 7 - Changes in prostate volume from baseline one month after treatment

[0088] Table 8 - Changes in prostate volume from baseline two months after treatment

[0089] 13.2.1.5. Maximum urinary flow rate analysis Maximum urinary flow rate (Qmax) is an important quantitative indicator for assessing lower urinary tract function, referring to the highest urine flow velocity during urination. In normal adult males, the maximum urinary flow rate is ≥15 ml / s. A Qmax <15 ml / s suggests possible benign prostatic hyperplasia or urethral obstruction. An increase in Qmax indicates improved lower urinary tract function.

[0090] Analysis of the maximum urinary flow rate in 60 patients showed that after two months of treatment, the maximum urinary flow rate increased by 5.61 ml / s from baseline after one month of treatment, an increase of 65%, which was statistically significant (P<0.01); after two months of treatment, the maximum urinary flow rate increased by 6.09 ml / s from baseline, an increase of 69%, which was also statistically significant (P<0.01). This indicates a significant improvement in patients' urinary difficulties. See Tables 9 and 10 for details. Note: * indicates statistically significant difference; ** indicates highly statistically significant difference. Table 9 - Changes in maximum urinary flow rate from baseline one month after treatment

[0091] Table 10 - Changes in maximum urinary flow rate from baseline after two months of treatment

[0092] 13.2.1.6. Summary of Effectiveness The results showed that the water pills of this invention, when used alone, significantly improved clinical symptoms such as urinary frequency, urgency, hesitancy, and incomplete urination. After treatment, patients' International Prostate Symptom Score (IPSS score), prostate volume (PV), maximum urinary flow rate (Qmax), and quality of life scores were significantly reduced, with highly significant differences before and after treatment (P<0.01). This indicates that the water pills of this invention are significantly effective in treating benign prostatic hyperplasia.

[0093] 13.2.2. Security Analysis 13.2.2.1. Dosage The medication adherence of the 60 patients was good, falling within the 80%-120% adherence range.

[0094] 13.2.2.2. Adverse Event Analysis The water pills of the present invention have good safety, and no adverse events occurred during the medication period.

[0095] 13.2.2.3. Laboratory tests related to safety During the experiment, blood routine tests (WBC, RBC, NEUT%, LYMPR%, HB, PLT), urine routine tests (PRO, LEU, ERY), liver function tests (ALT, AST, TBIL, γ-GT), kidney function tests (UREA or BUN, Cr), coagulation tests (TT, PT, APTT, FIB), and 12-lead electrocardiogram were monitored, and no significant abnormalities were found.

[0096] 13.2.2.4. Security Summary No adverse events occurred in the 60 patients included in the trial.

[0097] Overall, the water pellets of the present invention demonstrate good safety and tolerability.

[0098] 14. Clinical Trial Conclusions The results showed that the water pills of this invention, used alone, significantly improved clinical symptoms such as urinary frequency, urgency, hesitancy, and incomplete urination. After treatment, patients' International Prostate Symptom Score (IPSS) and prostate volume (PV) were significantly reduced, maximum urinary flow rate (Qmax) was significantly increased, and quality of life scores were significantly improved, with highly significant differences before and after treatment (P<0.01). No adverse events occurred in the 60 patients included in the trial. This demonstrates that the water pills of this invention for treating benign prostatic hyperplasia have outstanding substantial features and significant progress compared to existing technologies.

[0099] Compared to current first-line drugs for treating BPH, 5-α reductase inhibitors and α-receptor blockers have significant advantages. Symptom improvement and onset time are comparable to tamsulosin, with a maximum urinary flow rate increase (69%) higher than tamsulosin's maximum (44%). Compared to finasteride, prostate volume decreases more rapidly. Finasteride, after 48 months of follow-up, showed a 18% reduction in prostate volume; after one year of treatment, the prostate volume no longer decreased significantly, and statistically significant symptom improvement was observed from the 8th month. In contrast, the formulation of this invention showed a significant decrease in prostate volume (10%) in the first month of use. The maximum urinary flow rate increased by 6.09 ml / s, higher than finasteride's maximum of 1.6 ml / s. Regarding safety, no adverse events occurred in the 60 patients included in the trial.

[0100] II. Pharmacodynamic studies of the pharmaceutical compositions of the present invention (a) Preparation of drugs for pharmacodynamic research (the powder of this invention) 1. Weigh the active pharmaceutical ingredient conforming to the pharmaceutical composition of the present invention. Astragalus membranaceus 135kg, American cockroach 108kg, Aconitum carmichaelii 75kg, Eupolyphaga sinensis 75kg, Curcuma longa 45kg, Glycyrrhiza uralensis 12kg.

[0101] 2. Preparation of powder Step 1: Grind the above 6 ingredients into powder, pass through an 80-mesh sieve, and mix evenly.

[0102] Step 2: Dispense the powder into 300g bags to obtain 1500 bags of the powder of this invention for animal testing.

[0103] (II) Pharmacodynamic studies of the pharmaceutical compositions of the present invention Experimental Unit: Shandong Academy of Medical Sciences Experiment leader: Wang Fuwen 1. Effect of oral administration of the powder of the present invention on benign prostatic hyperplasia in castrated rats. Experimental objective: To observe the effect of oral administration of the powder of the present invention on benign prostatic hyperplasia in castrated rats.

[0104] Experimental materials and reagents: The powder of this invention, specification: 300g / bag, content: astragaloside A content 0.272mg / g, batch number: 231101; distilled water, Jinan Mingxin Distilled Water Sales Department, specification: 25L / barrel, batch numbers: 20240913, 20241111.

[0105] Main instrument: SL202N electronic balance.

[0106] Animals: Male SD rats, 240-260g, Jinan Pengyue Experimental Animal Breeding Co., Ltd.

[0107] Experimental Methods: Quarantined male SD rats were randomly divided into a sham-operated control group (n=10) and a prostate hyperplasia (BPH) model group (n=50) according to body weight using the Latin method. Rats were anesthetized by intraperitoneal injection of 5% acetaminophen, fixed on the operating table, and the surgical area was routinely disinfected. Under aseptic conditions, both testes were removed from the model group via the scrotum, and the stumps were ligated to ensure hemostasis. The skin was then sutured. Rats in the sham-operated control group underwent sham surgery. Antibiotics were administered for 3 consecutive days post-surgery to prevent infection. One week post-surgery, on day 8, castrated rats that had recovered well were selected and subcutaneously injected daily with testosterone propionate solution (dissolved in olive oil) at a dose of 4.0 mg / kg for 30 days to establish the prostate hyperplasia model. Simultaneously, the sham-operated control group received an equal volume of olive oil subcutaneously.

[0108] Ten rats were selected as the sham-operated control group, and forty rats with better recovery were selected as the model group. Male animals were ranked by weight from largest to smallest and divided into four groups using the Latin method: the model control group, the low-dose group, the medium-dose group, and the high-dose group of the powder of this invention, with ten rats in each group. All treatment groups were administered different concentrations of the drug solution by gavage simultaneously with model establishment. The sham-operated control group and the model control group received the same volume of distilled water. The drug administration volume was 20 ml / kg. Administered once daily for 30 consecutive days. On the second day after the last administration (after fasting but with free access to water for 12 hours), the rats were weighed and sacrificed. The prostate was quickly harvested and its wet weight was measured, and the prostate index was calculated (prostate index = prostate wet weight g / rat body weight g). The prostate was divided into two parts. 300 mg of the left lobe of the prostate was added to 1 ml of ice-cold physiological saline, homogenized at 4°C, centrifuged at 3000 rpm for 15 min, and the supernatant of the prostate tissue homogenate was collected to detect testosterone (T), estradiol (E2), and epidermal growth factor (EGF) in the prostate tissue. The right prostate tissue was harvested for histopathological examination.

[0109] Experimental results: (1) Prostate index Compared with the sham-operated control group, after 30 days of administration, the body weight of rats in the model control group was significantly reduced (P < 0.01); the wet weight of the prostate and the prostate index were significantly increased, and the difference was statistically significant (P < 0.01). Compared with the model control group, during the administration period, there was no significant difference in body weight among the low-dose, medium-dose, and high-dose groups of the powder of the present invention (P > 0.05); after 30 days of administration, the wet weight of the prostate and the prostate index of rats in the high-dose group of the powder of the present invention were significantly reduced, and the difference was statistically significant (P < 0.05); although there was no significant difference in wet weight of the prostate and the prostate index between the low-dose and medium-dose groups of the powder of the present invention (P = 0.342 and P = 0.355, P = 0.257 and P = 0.167), there was a certain decreasing trend. The powder of the present invention has a dose-related effect on the wet weight of the prostate and the prostate index of rats. See Table 11 for details. Note: Compared with the sham-operated control group, ** P < 0.01; compared with the model control group, # P < 0.05.

[0110] Table 11. Prostate wet weight and prostate index of rats in each group after 30 days of drug administration (n=10)

[0111] (2) Compared with the sham-operated control group, after 30 days of administration, the levels of testosterone (T), estradiol (E2), and epidermal growth factor (EGF) in the prostate tissue of rats in the model control group were significantly increased (P < 0.05), while the estradiol (E2) content showed no significant difference (P > 0.05). Compared with the model control group, after 30 days of administration, there were no significant differences in the levels of testosterone (T) and estradiol (E2) in the prostate tissue of rats in the low-dose, medium-dose, and high-dose groups of the powder of the present invention (P > 0.05); the levels of epidermal growth factor (EGF) in the prostate tissue of rats in the low-dose, medium-dose, and high-dose groups of the powder of the present invention were significantly decreased (P < 0.01). See Table 12 for details. Note: Compared with the normal control group, * P < 0.05; compared with the model control group, # P < 0.05 ## P < 0.01.

[0112] Table 12. Testosterone (T) and estradiol (E2) levels in prostate tissue of rats in each group. and epidermal growth factor (EGF) content (n=10)

[0113] (3) Histopathological examination of the prostate tissue Sham surgery control group: The prostate epithelium is a single layer of low columnar or single layer of cuboidal structure, the acini are loosely arranged, a small amount of eosinophilic secretions can be seen in the lumen, and a small number of acini epithelium form folds that protrude into the glandular lumen.

[0114] Model control group: Prostatic acinar epithelial hyperplasia, increased and thickened acinar epithelial cells, which may protrude into the glandular lumen in a papillary manner, with slightly increased basophilicity of the cytoplasm and tightly arranged acini.

[0115] In the low-dose group of the powder of this invention: the prostatic acini are tightly arranged, the acinar epithelial cells increase to form folds protruding into the glandular lumen, the cells are tall columnar, and the cytoplasm basophilicity is slightly enhanced. Compared with the model control group, no significant difference was observed in the prostate. In the medium-dose group of the powder of this invention: focal hyperplasia of the prostate, the acinar epithelial cells increase to form folds protruding into the glandular lumen, and the acini are arranged more loosely. Compared with the model control group, the degree of prostate hyperplasia was reduced. In the high-dose group of the powder of this invention: focal hyperplasia of the prostate, the acinar epithelial cells increase to form folds protruding into the glandular lumen, and the acini are arranged more loosely. Compared with the model control group, the degree of prostate hyperplasia was reduced, and the hyperplasia area was shrunk. See Appendix. Figure 1-5 . Attached Figure Description

[0116] Figure 1 : Histopathological examination results of the prostate tissue in the sham surgery control group. The prostate epithelium is a single layer of low columnar or cuboidal epithelium, with loosely arranged acini. A small amount of eosinophilic secretions can be seen in the lumen, and a few acini of epithelium form folds protruding into the glandular lumen. (HE×100) Figure 2 : Histopathological examination results of prostate tissue in the model control group. Prostate acinar epithelial hyperplasia was observed, with increased and thickened acinar epithelial cells that could protrude into the glandular lumen in a papillary manner. The cytoplasm showed slightly increased basophilicity, and the acini were densely arranged. (HE×100) Figure 3 The results of histopathological examination of the prostate tissue in the low-dose group of the powder of this invention: The prostate acini were tightly arranged, with an increase in acinar epithelial cells forming folds protruding into the glandular lumen. The cells were tall columnar, and the cytoplasm showed slightly increased basophilicity. No significant differences were observed compared with the model control group. (HE×100) Figure 4 The results of histopathological examination of the prostate tissue in the medium-dose group of the powder of this invention: Focal hyperplasia of the prostate, with increased acinar epithelial cells forming folds protruding into the glandular lumen, and the acinar arrangement being relatively loose. Compared with the model control group, the degree of hyperplasia was reduced, and the area of ​​hyperplasia was smaller. (HE×100) Figure 5 , Figure 11 The results of histopathological examination of the prostate tissue in the high-dose group of the powder of this invention: Focal hyperplasia of the prostate, with increased acinar epithelial cells forming folds protruding into the glandular lumen, and the acinar arrangement being relatively loose. Compared with the model control group, the degree of prostate hyperplasia was reduced, and the area of ​​hyperplasia was smaller. (HE×100) Experimental conclusion: Under the experimental conditions, the low, medium and high dose groups of the powder of the present invention all have therapeutic effects on benign prostatic hyperplasia in castrated rats.

[0117] 2. Effect of oral administration of the powder of the present invention on benign prostatic hyperplasia in non-castrated rats. Experimental objective: To observe the effect of oral administration of the powder of the present invention on benign prostatic hyperplasia in non-castrated rats.

[0118] Experimental materials and reagents: The powder of this invention, specification: 300g / bag, content: astragaloside A content 0.272mg / g, batch number: 231101; distilled water, Jinan Mingxin Distilled Water Sales Department, specification: 25L / barrel, batch numbers: 20241111, 20250114.

[0119] Main instrument: SL202N electronic balance.

[0120] Animals: Male SD rats, 250–270 g, Jinan Pengyue Experimental Animal Breeding Co., Ltd.

[0121] Experimental method: Fifty male animals that passed quarantine and were excluded due to excessive or insufficient weight were selected. The male animals were sorted by weight from largest to smallest and divided into five groups according to the Latin method: normal control group, model control group, low-dose powder group of the present invention (1.2g crude drug / kg), medium-dose powder group of the present invention (2.4g crude drug / kg), and high-dose powder group of the present invention (4.8g crude drug / kg), with a total of 10 animals per group.

[0122] The normal control group received a subcutaneous injection of an equal volume of 0.9% sodium chloride solution every 1 day, while the other four groups of rats received a subcutaneous injection of testosterone propionate 50 mg / kg every 1 day at a volume of 1.0 ml / kg for 28 consecutive days to establish a non-castrated rat model of benign prostatic hyperplasia. Simultaneously with modeling, each treatment group was administered a different concentration of the drug solution by gavage, while the normal and model control groups received an equal volume of distilled water at a volume of 20 ml / kg. The administration was once daily for 30 consecutive days. On the second day after the last administration (after a 12-hour fast with free access to water), the rats were weighed, sacrificed, and their prostates were quickly harvested and weighed wet. The prostate index was calculated (prostate index = prostate wet weight (g) / rat body weight (g) × 100%). The prostate was divided into two parts, referred to as the left lobe. 300 mg of the left prostate tissue was added to 1 mL of ice-cold saline, homogenized at 4°C, and centrifuged at 3000 rpm for 15 min. The supernatant of the prostate tissue homogenate was collected, and testosterone (T), estradiol (E2), and epidermal growth factor (EGF) were detected in the prostate tissue. The right prostate tissue was taken for histopathological examination.

[0123] Experimental results: (1) Prostate index Compared with the normal control group, after 30 days of administration, the rats in the model control group showed a significant decrease in body weight, and a significant increase in prostate wet weight and prostate index, all of which were statistically significant (P < 0.01). Compared with the model control group, after 30 days of administration, there was no significant difference in body weight among the rats in each administration group (P > 0.05); although there was no significant difference in prostate wet weight and prostate index among rats in the low-dose group of the powder of the present invention (P > 0.05), there was a decreasing trend; the prostate wet weight of rats in the medium-dose and high-dose groups of the powder of the present invention was significantly reduced, and both were statistically significant (P < 0.05 and P < 0.01); the prostate index of rats in the high-dose group of the powder of the present invention was significantly reduced, and both were statistically significant (P < 0.05); although there was no significant difference in prostate index between the low-dose and medium-dose groups of the powder of the present invention (P > 0.05), both showed a decreasing trend. See Table 13 for details. Note: Compared with the normal control group, ** P < 0.01; compared with the model control group, # P < 0.05 ## P < 0.01.

[0124] Table 13. Prostate wet weight and prostate index in rats of each group (n=10)

[0125] (2) Content of testosterone (T), estradiol (E2) and epidermal growth factor (EGF) in prostate tissue Compared with the normal control group, after 30 days of drug administration, the levels of estradiol (E2) and epidermal growth factor (EGF) in the prostate tissue of rats in the model control group were significantly increased (P<0.01), while the level of testosterone (T) was not significantly different (P>0.05), but showed an increasing trend (P=0.081). Compared with the model control group, after 30 days of administration, the testosterone (T) content in the prostate tissue of rats in the medium-dose group of the powder of the present invention was significantly reduced (P < 0.01). Although there was no statistically significant difference in testosterone (T) content in the prostate tissue of rats in the low-dose and high-dose groups of the powder of the present invention (P > 0.05), both showed a decreasing trend (P = 0.113, P = 0.056, P = 0.325 and P = 0.061). Although there was no statistically significant difference in estradiol (E2) content in the prostate tissue of rats in the low-dose, medium-dose and high-dose groups of the powder of the present invention (P > 0.05), both the low-dose and high-dose groups showed a decreasing trend (P = 0.424 and P = 0.193). The epidermal growth factor (EGF) content in the prostate tissue of rats in the low-dose, medium-dose and high-dose groups of the powder of the present invention was significantly reduced (P < 0.01 and P < 0.05). See Table 14 for details. Note: Compared with the normal control group, **P < 0.01; compared with the model control group, # P < 0.05 ## P < 0.01. Groups with fewer animals were those where epidermal growth factor (EGF) levels were not detected.

[0126] Table 14. Testosterone (T) and estradiol (E2) levels in prostate tissue of rats in each group. and epidermal growth factor (EGF) content (n=10)

[0127] (3) Histopathological examination of the prostate tissue In the normal control group, rats showed focal hyperplasia of the prostate gland, with the acinar epithelium appearing as a single layer of low columnar or cuboidal epithelium. Numerous eosinophilic secretions were visible within the lumen, and a small portion of the acinar epithelium formed folds protruding into the glandular lumen. In the model control group, rats showed increased and thickened acinar epithelial cells, which could protrude into the glandular lumen in a papillary manner. The cells were tall columnar, with slightly increased basophilicity of the cytoplasm, and the acini were densely arranged. In the low-dose group of the powder of this invention, rats showed increased and thickened acinar epithelial cells, which could protrude into the glandular lumen in a papillary manner. The cells were tall columnar, with increased basophilicity of the cytoplasm, and the acini were densely arranged. Compared with the model control group, no significant difference was observed in the prostate gland. In the medium-dose group of the powder of this invention, rats showed acinar epithelial cells forming folds protruding into the glandular lumen. Compared with the model control group, the degree of acinar epithelial thickening was reduced. In the high-dose group of the powder of this invention, a small portion of acinar epithelial cells formed folds protruding into the glandular lumen, and the acini were loosely arranged. Compared with the model control group, the degree of acinar epithelial thickening was reduced, and the extent of hyperplasia was smaller. (See Appendix) Figure 6-10 .

[0128] Figure 6 : Histopathological examination results of prostate tissue in the normal control group. Focal hyperplasia of the prostate, with simple low columnar or simple cuboidal acinar epithelium, abundant eosinophilic secretions visible in the lumen, and a small portion of the acinar epithelium forming folds protruding into the glandular lumen. (HE×100) Figure 7 : Pathological examination results of prostate tissue in the model control group. The prostate acinar epithelial cells were increased and thickened, with multiple acinar epithelial projections into the glandular lumen in a papillary manner. The cells were tall columnar, with increased basophilicity of the cytoplasm, and the acini were densely arranged. (HE×100) Figure 8 The results of histopathological examination of the prostate tissue in the low-dose group of the powder of this invention: The prostate acinar epithelial cells were increased and thickened, and could protrude into the glandular lumen in a papillary manner. The cells were tall columnar, with increased basophilicity of the cytoplasm, and the acini were densely arranged. No significant difference was observed compared with the model group. (HE×100) Figure 9The results of histopathological examination of the prostate tissue in the medium-dose group of the powder of this invention show that the prostate acinar epithelial cells form folds protruding into the glandular lumen, and the degree of thickening of the acinar epithelium is reduced compared with the model control group. (HE×100) Figure 10 The results of histopathological examination of the prostate tissue in the high-dose group of the powder of this invention: A small number of acinar epithelial cells of the prostate formed folds protruding into the glandular lumen, and the acini were loosely arranged. Compared with the model control group, the degree of thickening of the acinar epithelium was reduced, and the area of ​​hyperplasia was shrunk. (HE×100) Experimental conclusion: Under the experimental conditions, the powder of the present invention has therapeutic effects on benign prostatic hyperplasia in non-castrated rats at low, medium and high doses.

[0129] III. Safety Study of the Pharmaceutical Composition of the Invention (a) Preparation of the drug for safety studies (the powder of this invention) 1. Weigh the active pharmaceutical ingredient conforming to the pharmaceutical composition of the present invention. Astragalus membranaceus 13.5kg, American cockroach 10.8kg, Aconitum carmichaelii 7.5kg, Eupolyphaga sinensis 7.5kg, Curcuma longa 4.5kg, Glycyrrhiza uralensis 1.2kg.

[0130] 2. Preparation of powder Step 1: Grind the above 6 ingredients into powder, pass through an 80-mesh sieve, and mix evenly.

[0131] Step 2: Dispense the drug into 300g bags for animal testing.

[0132] (II) Safety Study of the Pharmaceutical Composition of the Present Invention Experimental Unit: Shandong Academy of Medical Sciences Experiment leader: Wang Xiaobo 1. Toxicity test of the powder of the present invention administered to rats via gavage after a single dose. Experimental Objective: To observe the toxic reactions in rats after two oral administrations of the powder of this invention within 24 hours over a certain period of time, and to preliminarily elucidate the toxic effects and target organs of the powder of this invention. This also provides reference data for dose design in repeated-dose toxicity studies.

[0133] Experimental materials and reagents: The powder of this invention, specification: 300g / bag, content: astragaloside A content 0.272mg / g, batch number: 231101; distilled water, Jinan Mingxin Distilled Water Sales Department, specification: 25L / barrel, batch number: 20240318.

[0134] Main instruments: YP3001N electronic balance, YLS-27A automatic labeling instrument for rat and mouse tails.

[0135] Animals: SD rats, females 160-200g, males 200-250g, Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0136] Experimental Methods: Twenty qualified SD rats of appropriate age, half male and half female, were selected and divided into two groups using the Latin method according to the principle of balanced body weight: a solvent control group and a powder group of the present invention, with 5 rats / sex / group. The rats were administered the maximum dose method at a maximum volume of 20 ml / kg and a maximum gavage concentration of 0.3 g / ml, twice within 24 hours, with an interval of at least 5 hours, for a total dose of 12 g / kg / day (equivalent to 11.4 g crude drug / kg / day). The rats were observed for 14 consecutive days. The toxicity of the animals was observed after administration, and they were weighed before administration and on days 1, 3, 7, and 14 after administration. After the observation period, all rats were dissected, and the location, shape, size, color, texture, and presence of exudate, congestion, hemorrhage, edema, necrosis, and other changes in the organs were observed.

[0137] Experimental results: (1) General physical signs No obvious abnormalities were observed in either the powder group or the solvent control group of the present invention.

[0138] (2) Weight The rats in the solvent control group showed good weight gain, while no significant difference was observed between the powder group and the solvent control group (P > 0.05). Results are shown in Table 15. Note: P > 0.05, compared with the solvent control group.

[0139] Table 15. Rat body weight (n=5, unit: g)

[0140] (3) Autopsy After the observation period, the animals were necropsyd. The major organs of the heart, liver, spleen, lungs and kidneys of the animals in each group were found to be normal in texture and color, without swelling, adhesion or congestion, and no obvious abnormal changes were observed.

[0141] Experimental conclusion: When the powder of the present invention was administered to rats twice by gavage within 24 hours at a maximum gavage concentration of 0.3 g / ml and a maximum administration volume of 20 ml / kg, with an interval of approximately 5 hours, no obvious toxic reactions were observed. The maximum dosage of the powder of the present invention for rats is 12 g / kg / day (equivalent to 11.4 g crude drug / kg / day), which is approximately 53 times the proposed daily dose for human clinical use.

[0142] 2. Toxicity test of the powder of the present invention in rats administered by gavage for 26 weeks (repeated administration) Experimental objectives: To predict potential adverse clinical reactions caused by the powder of this invention; to determine the target organs or tissues for repeated administration of the drug; to determine the dose level at which no adverse clinical reaction was observed (No Observed Adverse Effect Level, NOAEL); to provide a safe dose range for subsequent clinical trials; and to provide a reference for the monitoring and prevention of adverse clinical reactions.

[0143] Experimental materials and reagents: The powder of this invention, specification: 300g / bag, content: astragaloside A content 0.272mg / g, batch number: 231101; distilled water, Jinan Mingxin Distilled Water Sales Department, specification: 25L / barrel, batch numbers: 20240318, 20240616, 20240702, 20240913.

[0144] Main instruments: YP3001N electronic balance, YLS-27A rat and mouse tail automatic labeler, LDZ5-2 low-speed automatic balancing centrifuge, 7180ISE Hitachi fully automated biochemical analyzer, XT-2000iv automated hematology analyzer, CS-2000i fully automated coagulation analyzer, CombiScan500 urine eleven-item analyzer, HM-2FN vortex mixer / magnetic stirrer, PL203 electronic balance, ALC-1100.2 electronic balance.

[0145] Animals: SD rats, females 160-200g, males 200-250g, Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0146] Experimental Methods: Quarantined animals were selected, and animals with excessively large or small weights were excluded. The weight difference between sexes was within 20% of the average weight. Females were ranked from smallest to largest weight, and males from largest to smallest weight. Animals were then divided into four groups according to the Latin method: a solvent control group (distilled water) and three dosage groups for the powder of this invention: low (1.5 g / kg / day), medium (4.5 g / kg / day), and high (9.0 g / kg / day). Each group consisted of 48 animals, half male and half female. The powder was administered twice daily by gavage, with an interval of at least 5 hours between doses, at a volume of 15 ml / kg per dose, for 26 weeks, followed by a 4-week observation period after drug withdrawal. Clinical observation, body weight, food intake, hematological examination, blood biochemistry, urinalysis, and ophthalmological examination were conducted during the experiment. Animals were euthanized at 13 weeks after administration (6 animals / sex / group), at the end of administration (12 animals / sex / group), and at the end of the recovery period (6 animals / sex / group). Gross necropsy was performed, major organs were weighed, organ-to-body weight coefficients and organ-to-brain weight coefficients were calculated, and histopathological examinations were conducted on relevant tissues and organs.

[0147] Animal group, sex, and number are shown in Table 16.

[0148] Table 16 Animal Group, Sex, and Number Table

[0149] Experimental results: (1) Circumstances of death During the experiment, animals in the high-dose group (4001, 4010, 4108, 4109, and 4115) died on days 63, 64, 174, 162, and 100, respectively; animals in the medium-dose group (3008, 3010, and 3118) died on days 125, 125, and 49, respectively; animals in the low-dose group (2017 and 2122) died on days 76 and 136, respectively; and animal in the solvent control group (1119) died on day 162. Autopsy revealed that the lungs of animals 2017, 2122, 3008, 3010, 3118, 4108, 4109, and 4115 were significantly swollen, with blunted edges and a grayish-white color. The lungs of animals 1119, 4001, and 4010 were dark red. Among them, animal 4010 had a ruptured esophagus. Histopathological results showed that the lungs of all animals had diffuse vasodilation and congestion. The cause of death in all cases was improper gavage, which was unrelated to the toxicity of the powder of this invention.

[0150] (2) General observation During the trial, no drug-related abnormal symptoms were observed in any of the dosage groups; no abnormalities were observed in the solvent control group. No abnormalities were observed in any of the groups during the recovery period.

[0151] (3) Weight During the administration period, in the high-dose group, the weight gain of female rats at 7 weeks of administration was statistically significant compared with the solvent control group (P < 0.05), while the weight of male rats showed a decreasing trend during the administration period. The weight gain at 1-13 weeks of administration (weight loss of 6%-10%) and at 1, 2, and 8 weeks of administration was statistically significant compared with the solvent control group (P < 0.05). In the medium-dose group, the weight gain of female rats at 17 weeks of administration was statistically significant compared with the solvent control group (P < 0.01), while there was no significant difference in weight and weight gain between male rats and the solvent control group (P > 0.05). In the low-dose group, the weight gain of female rats at 9 weeks of administration was statistically significant compared with the solvent control group (P < 0.01), while there was no significant difference in weight and weight gain between male rats and the solvent control group (P > 0.05).

[0152] During the recovery period, there were no significant differences in body weight and weight gain between the high-, medium-, and low-dose groups and the solvent control group (P > 0.05).

[0153] Analysis of food intake and weight gain results suggests that the weight loss in male rats is related to the relatively large dosage of the powder in this invention, and the weight can return to normal after drug withdrawal.

[0154] (4) Food intake During the dosing period, at the high dose, female rats showed a statistically significant reduction in food intake (9%–12%) at 7, 9, 10, 13, 14, and 25 weeks compared to the solvent control group (P < 0.05 or 0.01), while male rats showed a statistically significant reduction in food intake (11%–21%) at 1, 3–14, and 18–22 weeks compared to the solvent control group (P < 0.05 or 0.01). At the medium dose, female rats showed a statistically significant reduction in food intake (7%–9%) at 6, 9, and 13 weeks compared to the solvent control group (P < 0.05 or 0.01), while no significant difference was observed in food intake in male rats compared to the solvent control group (P > 0.05). In the low dose group, no significant difference was observed in food intake in either male or female rats compared to the solvent control group (P > 0.05).

[0155] During the recovery period, no statistical comparison was made between the dosage groups and the solvent control group.

[0156] Analysis suggests that the reduced food intake is related to the relatively large dosage of the powder in this invention, and the intake returned to normal after discontinuation of the medication.

[0157] (5) Hematological examination After 13 weeks of administration, no significant differences were observed between the female rats in each dose group and the solvent control group (P > 0.05); in male rats, the high-dose group showed statistically significant differences in NEUT% (↑128%) and LYM% (↓29%) compared with the solvent control group (P < 0.05 or 0.01), while no significant differences were observed between the medium- and low-dose groups and the solvent control group (P > 0.05). At the end of administration and the end of the recovery period, there were no significant differences between the dosage groups and the solvent control group (P>0.05).

[0158] Analysis suggests that changes in NEUT% and LYM% did not show a significant time-response relationship; the differences were statistically significant but not biologically significant.

[0159] (6) Blood biochemistry tests Dosage 13 weeks In the high-dose group, female rats showed statistically significant differences in ALB (↓12%) and K+ (↑10%) compared to the solvent control group (P<0.05 or 0.01), while male rats showed statistically significant differences in GGT (↑155%) compared to the solvent control group (P<0.05). In the medium-dose group, female rats showed statistically significant differences in K+ (↑10%) compared to the solvent control group (P<0.01), while male rats showed statistically significant differences in TP (↑9%) compared to the solvent control group (P<0.05). In the low-dose group, female rats showed statistically significant differences in CK (↓) compared to the solvent control group (P<0.05), while no significant difference was observed between male rats and the solvent control group (P>0.05).

[0160] End of administration No significant differences were observed between the dosage groups and the solvent control group (P>0.05).

[0161] Recovery period ended There were no significant differences between the high- and medium-dose groups and the solvent control group (P>0.05); in the low-dose group, the K+ (↑13%) in female rats was significantly different from that in the solvent control group (P<0.05), while there was no significant difference between male rats and the solvent control group (P>0.05).

[0162] The analysis suggests that the changes in the above indicators were small, with no obvious time-response or dose-response relationship observed. The differences were statistically significant but not biologically significant.

[0163] (7) Urine test Dosage 13 weeks No significant differences were observed between the dosage groups and the solvent control group (P>0.05).

[0164] The urine samples from all groups were clear and pale yellow in color upon examination.

[0165] End of administration In the high- and medium-dose groups, there were no significant differences in the levels of male and female rats compared with the solvent control group (P > 0.05); in the low-dose group, the levels of PRO in female rats were statistically significant compared with the solvent control group (P < 0.05), while there were no significant differences in the levels of PRO in male rats compared with the solvent control group (P > 0.05).

[0166] The urine samples from all groups were clear and pale yellow in color upon examination.

[0167] Recovery period ended No significant differences were observed between the dosage groups and the solvent control group (P>0.05).

[0168] The urine samples from all groups were clear and pale yellow in color upon examination.

[0169] At the end of administration, the PRO positivity rate in the low-dose group was lower than that in the solvent control group. This difference was statistically significant but not biologically significant.

[0170] (8) Ophthalmological examination No abnormalities were observed in any group at the end of the administration and recovery period.

[0171] Pathological examination (9.1) Gross Observation of Anatomy No abnormalities were observed in any group at the end of the administration and recovery period.

[0172] (9.2) Organ weight and relative weight (organ-to-body ratio, organ-to-brain ratio) After 13 weeks of administration: at high and medium doses, there were no significant differences between male and female rats and the solvent control group (P>0.05); at low dose, there were no significant differences between female rats and the solvent control group (P>0.05), but the adrenal glands (visceral-to-brain ratio increased by 24%) in male rats were statistically significant compared with the solvent control group (P<0.05).

[0173] At the end of administration: At the high dose, the liver size of female rats (viscera-to-body ratio increased by 12%) was statistically significant compared with the solvent control group (P < 0.01), while no significant difference was observed between male rats and the solvent control group (P > 0.05); At the medium dose, no significant difference was observed between female rats and the solvent control group (P > 0.05), while the liver size of male rats (viscera-to-body ratio increased by 13%) was statistically significant compared with the solvent control group (P < 0.05); At the low dose, no significant difference was observed between male and female rats and the solvent control group (P > 0.05).

[0174] End of recovery period: No significant differences were observed between male and female rats at each dose and the solvent control group (P>0.05).

[0175] No significant time-response or dose-response relationship was observed in the adrenal gland-to-brain ratio of male rats. The liver of male and female rats differed only in the organ-to-body ratio, and no significant difference was found in the organ-to-brain ratio by weight. Combined with the histopathological examination results, no histopathological changes were found in the above organs. The analysis concluded that the differences were statistically significant but not biologically significant.

[0176] Experimental Conclusion: Under the conditions of this experiment, SD rats were administered the powder of this invention by gavage at doses of 1.5, 4.5, and 9.0 g / kg / day (equivalent to 1.4, 4.3, and 8.6 g crude drug / kg / day) for 26 weeks, followed by a 4-week recovery period after drug withdrawal. No drug-related toxic reactions were observed. The no-adverse-effect level (NOAEL) in rats was 9.0 g / kg / day, approximately 40 times the planned daily dose for human clinical use.

[0177] Safety studies have shown that the pharmaceutical composition of the present invention has good safety.

[0178] The present invention will be further illustrated by the following embodiments. These embodiments are only used to further illustrate and explain this application and are not intended to limit the present invention. Detailed Implementation

[0180] 1. Weigh the raw materials Astragalus membranaceus 135kg, American cockroach 108kg, Aconitum carmichaelii 75kg, Eupolyphaga sinensis 75kg, Curcuma longa 45kg, Glycyrrhiza uralensis 12kg.

[0181] 2. Preparation of powder The above 6 ingredients are pulverized, passed through an 80-mesh sieve, mixed evenly, and packaged into 5g bags to obtain a powder for 1000 people for one month.

[0182] Dosage: 3 times a day, 1 sachet each time; take with warm water.

[0183] Example 2: Preparation of the small honey pills of the present invention 1. Weigh the raw materials Astragalus membranaceus 27kg, American cockroach 21.6kg, Aconitum carmichaelii 15kg, Eupolyphaga sinensis 15kg, Curcuma longa 9kg, Glycyrrhiza uralensis 2.4kg.

[0184] 2. Preparation of small honey pills The above 6 ingredients are pulverized, passed through an 80-mesh sieve, mixed evenly, and then 90 kg of refined old honey cooled to 60℃ is added and mixed evenly. The mixture is then processed into small honey pills with a diameter of about 5 mm using a small honey pill machine, dried at 60℃ or below for 6 hours, and packaged into 10g / bags.

[0185] Dosage: 3 times a day, 1 sachet each time; take with warm water.

[0186] Example 3: Preparation of the water pills of the present invention 1. Weigh the raw materials Astragalus membranaceus 4.0kg, American cockroach 3.0kg, Aconitum carmichaelii 2kg, Eupolyphaga sinensis 2kg, Curcuma longa 1.4kg, Glycyrrhiza uralensis 0.37kg.

[0187] 2. Preparation of water pills The above six ingredients are pulverized, passed through an 80-mesh sieve, mixed evenly, and then, using purified water as a binder, hand-rolled into pills with a diameter of approximately 4mm using a medicine tray. The pills are then dried. They are packaged in 5g bags.

[0188] Dosage: 3 times a day, 1 sachet each time; take with warm water.

[0189] Example 4: Preparation of the water pellets of the present invention 1. Weigh the raw materials Astragalus membranaceus 4.7kg, American cockroach 3.8kg, Aconitum carmichaelii 3kg, Eupolyphaga sinensis 3kg, Curcuma longa 1.9kg, Glycyrrhiza uralensis 0.95kg.

[0190] 2. Preparation of water pills The above 6 ingredients are pulverized, passed through an 80-mesh sieve, and mixed evenly. Using purified water as a binder, they are mixed in a mixer until they form a soft material that can be formed into a ball when squeezed but crumbles when lightly pressed. The mixture is then made into water pellets with a diameter of about 3mm using a water pelleting machine, dried at a temperature below 60℃, and packaged into 5g bags.

[0191] Dosage: 3 times a day, 1 sachet each time; take with warm water.

[0192] Example 5: Preparation of the powder of the present invention 1. Weigh the raw materials Astragalus membranaceus 4.7kg, American cockroach 3.0kg, Aconitum carmichaelii 3kg, Eupolyphaga sinensis 2kg, Curcuma longa 1.5kg, Glycyrrhiza uralensis 0.4kg.

[0193] 2. Preparation of powder The above 6 ingredients are pulverized, passed through an 80-mesh sieve, mixed evenly, and packaged into 5g bags to obtain a one-month supply of powder for one person.

[0194] Dosage: 3 times a day, 1 sachet each time; take with warm water.

[0195] Example 6 A pharmaceutical composition for treating benign prostatic hyperplasia, comprising the following ingredients in the specified weight ratios: Astragalus membranaceus 4.0-4.7g, American cockroach 3.0-3.8g, Aconitum carmichaelii 2-3g, Eupolyphaga sinensis 2-3g, Curcuma longa 1.4-1.9g, and Glycyrrhiza uralensis 0.37-0.95g.

[0196] Prepared into powder or pill form using pharmaceutical techniques known to those skilled in the art. Dosage: 5g three times daily, dissolved in warm water.

Claims

1. A pharmaceutical composition and its formulation for treating benign prostatic hyperplasia, characterized in that: It is composed of the following raw materials: Astragalus membranaceus 4.0-4.7 parts, American cockroach 3.0-3.8 parts, Aconitum carmichaelii 2-3 parts, Eupolyphaga sinensis 2-3 parts, Curcuma longa 1.4-1.9 parts, and Glycyrrhiza uralensis 0.37-0.95 parts.

2. A pharmaceutical composition and its formulation for treating benign prostatic hyperplasia according to claim 1, characterized in that: The preferred composition is as follows: Astragalus membranaceus 4.5 parts, American cockroach 3.6 parts, Aconitum carmichaelii 2.5 parts, Eupolyphaga sinensis 2.5 parts, Curcuma longa 1.5 parts, and Glycyrrhiza uralensis 0.4 parts.

3. A pharmaceutical composition and its formulation for treating benign prostatic hyperplasia according to claim 1, characterized in that: Prepared into powders or pills.

4. A pharmaceutical composition and its formulation for treating benign prostatic hyperplasia according to claim 3, characterized in that: Preferred pills.

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