Pharmaceutical use of azvudine drug

Abstract

A use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof or an isotopically labeled compound thereof in the preparation of a drug for preventing or treating prostate-related diseases.

Description

Pharmaceutical uses of azvudine Technical Field

[0001] This invention relates to the use of compounds of formula (I) or pharmaceutically acceptable salts thereof, or isotopically labeled compounds thereof, in the preparation of medicaments for the prevention or treatment of prostate-related diseases. Background Technology

[0002] Benign prostatic hyperplasia (BPH) is a common disease affecting the physical and mental health of middle-aged and elderly men. With the increasingly fast pace of life, more and more young men are experiencing symptoms such as urinary urgency, frequency, and incomplete emptying. Benign prostatic hyperplasia is becoming more common. Data shows that the incidence of benign prostatic hyperplasia is increasing worldwide. BPH is a common disease affecting the physical and mental health of middle-aged and elderly men.

[0003] Chronic prostatitis (CP) is a common disease in urology, including type II chronic bacterial prostatitis and type III CP / chronic pelvic pain syndrome. The main clinical manifestations include pelvic pain and discomfort, such as painful ejaculation and lower abdominal pain; lower urinary tract symptoms, such as urinary frequency, urgency, and dysuria; emotional symptoms, such as insomnia, anxiety, and depression; and sexual dysfunction, such as decreased libido. The incidence rate of this disease ranges from 6.0% to 32.9%, and its etiology is complex.

[0004] Prostate-specific antigen (PSA) is a glycoprotein produced by prostate cells and is currently the most commonly used serum biomarker for prostate cancer. When the prostate gland is abnormal, such as in cases of prostate cancer, an excess of prostate cells, excessive PSA production, or PSA infiltration into the bloodstream, measurable PSA levels in the blood may increase. Higher than normal PSA levels may indicate a problem with the prostate, including but not limited to cancer.

[0005] Therefore, finding new drug targets and new treatment methods for prostate-related diseases is a very urgent task.

[0006] Azvudine (FNC) has been approved for marketing as a treatment for HIV and COVID-19, and its safety has been guaranteed. Summary of the Invention

[0007] In order to find new therapeutic drugs for prostate-related diseases, the inventors tested the effects of azvudine-like drugs on various functional parameters of the prostate in model SD rats. The results showed that azvudine-like drugs had a significant ameliorative effect on prostate diseases in SD rats.

[0008] In view of this, this document provides, on one hand, the use of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or isotopically labeled compounds thereof, in the preparation of a medicament for the prevention or treatment of prostate-related diseases; on another hand, this document provides a method for the prevention or treatment of prostate-related diseases, comprising administering to a patient in need a therapeutically or preventively effective amount of the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or isotopically labeled compounds thereof; on yet another hand, this document provides the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or isotopically labeled compounds thereof, for the prevention or treatment of prostate-related diseases; and on yet another hand, this document provides a pharmaceutical composition comprising the compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or isotopically labeled compounds thereof, and optional excipients, said pharmaceutical composition for the prevention or treatment of prostate-related diseases.

[0009] The prostate-related diseases mentioned are selected from benign prostatic hyperplasia, prostatic hypertrophy, prostatitis, prostate cancer, and prostate damage or diseases related to elevated serum PSA levels.

[0010] Optionally, the prostatitis is selected from chronic nonbacterial prostatitis, which may be caused by factors such as poor lifestyle and dietary habits, and may be accompanied by symptoms such as frequent urination, urgency, difficulty urinating, and urinary retention.

[0011] The structural formula of equation (I) is as follows:

[0012] In formula (I),

[0013] R 1 For H or R 5 -CO-;

[0014] R 2 It can be: H, azide, C1-C6 alkyl (e.g., methyl, ethyl), C1-C6 alkoxy (e.g., methoxy, ethoxy), C2-C6 alkynyl (e.g., ethynyl), C2-C6 alkenyl (e.g., vinyl), or halo-C1-C6 alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl);

[0015] R 3 The substituent is H, optionally substituted R-CO-, optionally substituted RO(C=O)-, or optionally substituted RNH-CO-, wherein R is a C1-C6 alkyl group (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, etc.), and the substituent is selected from C1-C6 alkyl groups, halogens (e.g., F, Cl), CN, N3, and OR. 5 ;

[0016] R4 It can be H, OH, halogen (e.g., F), C1-C6 alkyl (e.g., methyl, ethyl), or C1-C6 alkoxy (e.g., methoxy, ethoxy);

[0017] B is selected from:

[0018] Where X1 is -OH, -NH2, R 5 CONH-, R 5 COO- or R 5 O(C=O)NH-;

[0019] X2 represents OH, SH, NH2, and R. 5 COO-, R 5 COS-, R 5 CONH2- or R 5 O(C=O)NH-;

[0020] X3 is H, F, OH or NH2;

[0021] Y is either CH or N;

[0022] Z is H, OH, or F;

[0023] Each R 5 Each is independently selected from H, C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl), C2-C6 ynyl (e.g., ethynyl), C2-C6 alkenyl (e.g., vinyl), halo-C1-C6 alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl), optionally C 1-6 Alkyl, C 1-6 Alkyl, CN, N3, OH, NH2, halogen-substituted (e.g., F, Cl, Br, I) phenyl groups, optionally C-substituted 1-6 Alkyl, C 1-6 Naphthyl groups substituted with alkoxy groups, CN, N3, OH, NH2, or halogens (e.g., F, Cl, Br, I).

[0024] Optionally, in equation (I),

[0025] R 1 For: H;

[0026] Optionally, R 1 For H or R 5 -CO-;

[0027] Optionally, R 2 It is: H, azide, or C2-C6 ynyl (e.g., ethynyl), optionally, R 2 It is: azide group;

[0028] Optionally, R 3For H;

[0029] Optionally, R 4 It can be H, OH, or a halogen (e.g., F);

[0030] Optionally, R 4 For H;

[0031] Optionally, B is selected from:

[0032] Where X1 is -OH or -NH2;

[0033] Optionally, X1 is NH2;

[0034] X2 is OH or NH2;

[0035] Optionally, X2 is NH2;

[0036] X3 is H, F, OH or NH2;

[0037] Optionally, X3 can be H or F;

[0038] Y is either CH or N;

[0039] Optionally, Y is CH;

[0040] Optionally, Z can be H, OH, or F;

[0041] Optionally, Z is F;

[0042] Optionally, each R 5 Each is independently selected from H, C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl), and halogenated C1-C6 alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl).

[0043] Preferably, in another aspect of the invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically labeled compound thereof, is selected from the following compounds or pharmaceutically acceptable salts thereof, or isotopically labeled compounds thereof: or

[0044] Preferably, the isotope-labeled compound is a deuterated compound.

[0045] Pharmaceutically acceptable salts of the compounds represented by formula (I) include, but are not limited to, salts formed by the compounds represented by formula (I) with the following acids: hydrochloric acid, hydrobromic acid, aminosulfonic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbic acid palmitic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine, etc.

[0046] Compounds of formula (I) can be purchased commercially or prepared by known methods.

[0047] The administration route can be oral or parenteral. The dosage form of the drug can be immediate-release, sustained-release, or controlled-release. Specific dosage forms can be various conventional dosage forms in the art; for example, oral preparations may include tablets, hard capsules, soft capsules, aqueous or oily suspensions, granules, emulsions, syrups, or elixirs. Injectable preparations may include injection solutions and powder for injection. Attached Figure Description

[0048] Figure 1 shows the weight changes of SD rats in each group in the example.

[0049] Figure 2 shows the bladder pressure test results of each group of SD rats in the examples.

[0050] Figure 3 is a bar chart of the intravesical pressure / mean arterial pressure ratio of SD rats in each group in the examples.

[0051] Figure 4 shows HE staining images of prostate inflammation in SD rats in each group in the examples.

[0052] Figure 5 is a bar chart of prostate inflammation scores for each group of SD rats in the embodiment based on Figure 4.

[0053] Figure 6 is a Masson staining image of the common iliac artery thickness test.

[0054] Figure 7 is a bar chart of the thickness of the left and right sides of the iliac artery, derived from Figure 6.

[0055] Figure 8 is a bar chart showing the PSA content in the serum of SD rats in each group before treatment and two months after treatment in the examples.

[0056] Figure 9 is a bar chart showing the changes in serum PSA levels in each group of SD rats before and two months after treatment, based on Figure 8. Detailed Implementation

[0057] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the scope of the invention.

[0058] Example:

[0059] I. Experimental Materials

[0060] The test drug, Azvudine (FNC), was sourced from Henan Zhenshi Biotechnology Co., Ltd.

[0061] The test drug, Tadalafil, was sourced from Shanghai Titan Technology Co., Ltd.

[0062] The experimental animals used were SD rats, which were obtained from Shanghai Jihui Experimental Animal Co., Ltd.

[0063] II. Drug Preparation

[0064] The test drug formulations are shown in Table 1.

[0065] Table 1

[0066] III. Experimental Grouping

[0067] After environmental adaptation, SD rats were randomly divided into 6 groups of 10 each: sham operation group, model group, Tadalafil (2 mg / kg), low-dose FNC group (0.25 mg / kg), and high-dose FNC group (0.5 mg / kg).

[0068] IV. Animal Modeling Surgery Procedure

[0069] Eighteen-month-old SD rats were anesthetized with salbutamol (40 mg / kg) and thiamethoxam (8 mg / kg). In the sham-operated group, animals underwent bilateral inguinal incision followed by immediate wound closure. In the model group, after bilateral inguinal incision, the femoral artery was isolated, and a thromboembolic catheter (E-060-2F) was inserted into the common iliac artery along the femoral artery. The catheter head was inflated with air, and mechanical friction (10 times) was applied to disrupt the inner wall of the common iliac artery. After completion, the catheter head was deflated and withdrawn through the femoral artery, and the femoral artery incision was repaired to restore blood supply to the lower limb. Intraoperative analgesia was administered (meloxacin, 2 MPk, sc). Postoperatively, the skin incision was cared for daily for 3 days to prevent infection (gentamicin injection, 4 MPk, sc). After modeling, the rats continued to be fed a high-fat diet for 8 weeks.

[0070] V. Experimental Methods and Results Discussion of Test Items

[0071] After successful modeling, oral administration was started in week 9 according to the experimental groups. Model rats were fed a high-fat diet containing 2% cholesterol, while Sham rats were fed a regular diet (containing 0.09% cholesterol). Tadalafil and FNC groups were administered the drug once a day at the doses described above for 8 weeks until the end of the experiment.

[0072] 1) Weight measurement

[0073] The changes in body weight of SD rats in each group are shown in Figure 1. The results indicate that all animals tolerated the drug well during administration.

[0074] 2) Bladder pressure test:

[0075] The right common carotid artery of each group of SD rats was isolated and inserted into the common carotid artery via a Millar catheter. The Millar catheter was connected to a pressure sensor of the Powerlab data analysis system to record changes in arterial blood pressure. A midline incision was then made in the lower abdomen to expose the bladder. A Millar catheter and a PE-50 silicone catheter were inserted into the urethra to the inlet of the prostate and bladder. The other end of the PE-50 silicone catheter was connected to a push pump syringe, and physiological saline was injected at a constant rate of 2 ml / min. The Millar catheter was connected to a Powerlab sensor to record intravesical pressure.

[0076] The results of bladder pressure tests in each group of SD rats are shown in Table 2, Figure 2, and Figure 3.

[0077] The results in Table 2 and Figure 2 show that the intravesical pressure of the Model rats was significantly higher than that of the Sham group. The mean intravesical pressure of the FNC 0.25 mg / kg group was significantly lower than that of the Model group, and the difference was statistically significant (14.43±2.13 vs 22.04±1.81, P<0.05). The FNC 0.5 mg / kg group and the Tadalafil group also showed a decreasing trend, indicating that the symptoms of dysuria were improved.

[0078] As shown in Table 2 and Figure 3, the bladder pressure and the corrected results of bladder pressure to mean arterial pressure (i.e., bladder pressure and the ratio of bladder pressure to mean arterial pressure) showed that the FNC 0.25 mg / kg group significantly reduced bladder pressure.

[0079] Table 2. Effects of intravesical pressure and intravesical pressure / mean arterial pressure ratio (Mean±SEM)

[0080] 3) Prostate inflammation detection:

[0081] SD rats were euthanized by whole-body perfusion with 500 ml of phosphate buffer for 10 minutes. Prostate tissue was then collected, weighed, and recorded. The prostate tissue (ventral side) was fixed with 4% paraformaldehyde (pH 7.4) and stained with hematoxylin and eosin (HE) to evaluate the degree of prostate inflammation.

[0082] The inflammation scores of the experimental SD rats are shown in Figures 4 and 5. The results show that the Model group had the highest inflammation score, while the scores of both FNC dose groups were very low, indicating that it has a certain inhibitory effect on prostate inflammation.

[0083] 4) Hyperplasia of the common iliac artery wall

[0084] The common iliac artery of experimental SD rats was fixed with 4% paraformaldehyde (pH 7.4) and then stained with Masson stain to evaluate the proliferation of the iliac artery wall.

[0085] The results of the common iliac artery thickness test are shown in Table 3, Figure 6 and Figure 7. The results show that, compared with the Sham group, the average thickness of the iliac artery endothelium on both sides of the SD rats in the Model group increased; the average thickness of the iliac artery endothelium on both sides of the Tadalafil group and the two FNC dosage groups was lower than that in the Model group, indicating that FNC has a significant ameliorative effect on the proliferation of the iliac artery vessel wall.

[0086] Table 3. Effects of iliac artery endothelial hyperplasia (Mean ± SEM)

[0087] The specific methods for HE staining and Masson staining are as follows:

[0088] 1.1 Organizational stability

[0089] Fresh tissue was immediately fixed in 4% formalin fixative for 24 hours.

[0090] 1.2 Tissue dehydration

[0091] The dehydration procedure for formalin-fixed paraffin-embedded tissues on an automatic dehydrator is shown in Table 4 below.

[0092] Table 4

[0093] 1.3 Tissue Embedding

[0094] Tissue embedding is performed on a paraffin embedding machine.

[0095] 1) Confirm the volume and temperature of the paraffin in the embedding machine;

[0096] 2) Turn on the light of the tissue embedding machine, put the sample into the heating cylinder, take out the embedding box, select the embedding base mold according to the size of the tissue, and add an appropriate amount of liquid paraffin into the embedding base mold;

[0097] 3) Place each tissue with the flat cut side down into the embedding mold and gently press it to the center of the bottom;

[0098] 4) Move the embedding mold from the hot stage to the rapid cooling point to fix the position of the tissue;

[0099] 5) Place the embedding cassette on the bottom mold and add an appropriate amount of molten, liquid paraffin to half the height of the embedding cassette;

[0100] 6) Move the bottom mold to the cooling table and wait for the paraffin wax to solidify before peeling the wax block off the bottom mold;

[0101] 7) Once finished, turn off the lights;

[0102] 8) Once finished, turn off the lights and clean the heated table;

[0103] 9) Clean the frost off the cooling table.

[0104] 1.4 Section Preparation

[0105] 1) Before sectioning, place the wax block on a -4℃ cold stage for 15-30 minutes;

[0106] 2) Place the paraffin block on a Leica HistoCore NANOCUT R, and section the tissue at a thickness of 4 μm;

[0107] 3) After the sections are spread in 42℃ hot water for 15 seconds, they are retrieved using a glass slide;

[0108] 4) Bake the glass slide in an oven at 62°C for 1 hour.

[0109] 1.5 HE staining

[0110] Table 5

[0111] 1.6 Masson staining

[0112] Table 6

[0113] 1.7 Slice Scanning and Analysis

[0114] All stained sections were scanned at 200x using a Zeiss Scan7 fully automated scanner. Semi-quantitative analysis was performed on HE-stained sections. The percentage of collagen fiber area was calculated using HALO software to analyze Masson-stained sections.

[0115] 5) Serum PSA test

[0116] Whole blood was collected from the first five animals in each group before administration and 2 hours after the last administration, into EDTA-K2 anticoagulant tubes, at least 200 μL per tube. The tubes were thoroughly mixed by inverting to ensure no clotting, and placed on wet ice at 2-8 degrees Celsius. A total of 20 samples were collected and centrifuged (4°C, 7500 rpm, 15 minutes) to collect at least 250 μL of serum for serum PSA detection.

[0117] Serum PSA levels were detected using ELISA. The detailed procedure is as follows:

[0118] 1.1 PSA test reagent formulation:

[0119] Table 7

[0120] 1.2 ELISA kit (PSA) testing steps:

[0121] 1) Prepare all reagents, working standards, and samples according to the instructions in the table above;

[0122] 2) Remove excess microporous strips from the plate frame, put it back into the foil bag containing desiccant, reseal it and return it to 4°C for storage;

[0123] 3) Add 100 μL of all samples or standards to the corresponding wells, seal, and incubate on a shaker at 400 rpm and 37°C for 2 hours; discard the liquid in the well plate and spin dry.

[0124] 4) Add 100 μL of biotin antibody to each well and incubate on a shaker at 37°C for 1 hour at 400 rpm.

[0125] 5) Then add 200 μL of 1X Wash Buffer to wash each well, repeat the washing 3 times; add 100 μL of HRP-avidin to each well, seal and incubate in the dark for 1 hour, then incubate on a shaker at 400 rpm and 37°C for 1 hour.

[0126] 6) Continue washing each well with 200 μL of 1X Wash Buffer, repeating the washing process 3 times; add 90 μL of TMB developer to each well and incubate in the dark on a shaker at 400 rpm for 15 minutes.

[0127] 7) Add 50 μL of stop solution to each well. Shake on a shaker for 1 min to mix thoroughly, and read the value at OD450 nm.

[0128] 1.3 Data Statistics

[0129] All data were entered into an Excel document and presented in Mean±SEM format. The one-way ANOVA Dunnett's test and the two-way ANOVA Dunnett's test were used for analysis and comparison.

[0130] The results are shown in Table 8, Figure 8, and Figure 9. The results indicate that the serum PSA level was higher in the Model group than in the Sham group. Compared with the Model group, the serum PSA levels decreased in the Tadalafil group and both FNC dosage groups. The decrease was more pronounced in the FNC 0.5 mg / kg group, showing a statistically significant difference compared to the Model group (119.26±12.89 vs 170.46±22.74, P<0.05).

[0131] Table 8. Effect of changes in serum total PSA levels (Mean ± SEM)

Claims

1. Use of a compound represented by Formula (I) or a pharmaceutically acceptable salt thereof, or an isotopically-labeled compound thereof, in the manufacture of a medicament for the prevention or treatment of a prostate-related disease, In formula (I), R 1 R is H, or R 5 -CO-; R 2 It can be: H, azide, C1-C6 alkyl (e.g., methyl, ethyl), C1-C6 alkoxy (e.g., methoxy, ethoxy), C2-C6 alkynyl (e.g., ethynyl), C2-C6 alkenyl (e.g., vinyl), or halo-C1-C6 alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl); R 3 is H, optionally substituted R-CO-, optionally substituted R-O(C=O)-, or optionally substituted RNH-CO-, wherein R is C1-C6alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, and the like), wherein, substituents are selected from the group consisting of C1-C6alkyl, halogen (such as F, Cl), CN, N3, and OR 5 ; R 4 is H, OH, halogen (e.g. F), Ci-C6alkyl (e.g. methyl, ethyl), or Ci-C6alkoxy (e.g. methoxy, ethoxy); B is selected from: wherein X1is -OH, -NH2, R 5 CONH-, R 5 COO- or R 5 O(C=O)NH-; X2 represents OH, SH, NH2, and R. 5 COO-, R 5 COS-, R 5 CONH2- or R 5 O(C=O)NH-; X3 is H, F, OH or NH2; Y is either CH or N; Z is H, OH, or F; Each R 5 Each is independently selected from H, C1-C6 alkyl (e.g., methyl, ethyl, propyl, isopropyl), C2-C6 ynyl (e.g., ethynyl), C2-C6 alkenyl (e.g., vinyl), halo-C1-C6 alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl), optionally C 1-6 Alkyl, C 1-6 Alkyl, CN, N3, OH, NH2, halogen-substituted (e.g., F, Cl, Br, I) phenyl groups, optionally C-substituted 1-6 Alkyl, C 1-6 Naphthyl groups substituted with alkoxy groups, CN, N3, OH, NH2, or halogens (e.g., F, Cl, Br, I); The prostate-related diseases mentioned are selected from benign prostatic hyperplasia, prostatic hypertrophy, prostatitis, prostate cancer, and prostate damage or diseases related to elevated serum PSA levels. Optionally, the prostatitis is chronic nonbacterial prostatitis.

2. Use according to claim 1, characterized in that, In formula (I), R 1 R is H; Optionally, R 1 is H or R 5 -CO-; Optionally, R 2 is: H, azido, or C2-C6alkynyl (e.g., ethynyl), optionally, R 2 is: azido; Optionally, R 3 is H; Optionally, R 4 is H, OH, or halogen (e.g., F); Optionally, R 4 is H; Optionally, B is selected from: Where X1 is -OH or -NH2; Optionally, X1 is NH2; X2 is OH or NH2; Optionally, X2 is NH2; X3 is H, F, OH or NH2; Optionally, X3 can be H or F; Y is either CH or N; Optionally, Y is CH; Optionally, Z can be H, OH, or F; Optionally, Z is F; Optionally, each R 5 each independently is selected from H, C1-C6alkyl (e.g., methyl, ethyl, propyl, isopropyl), haloC1-C6alkyl (e.g., 2-chloroethyl, 2-fluoroethyl, trifluoroethyl).

3. The use according to claim 1 or claim, wherein the compound of formula (I) is the following compound:

4. The use according to any one of claims 1-3, wherein the isotope-labeled compound is a deuterated compound.

5. The use according to any one of claims 1-4, wherein a pharmaceutically acceptable salt of the compound represented by formula (I) comprises a salt formed by the compound represented by formula (I) with the following acids: hydrochloric acid, hydrobromic acid, aminosulfonic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid, propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, ascorbic acid palmitic acid, salicylic acid, sulfosalicylic acid, 2-hydroxy-3-naphthoic acid, phthalic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, or leucine.

6. The use according to any one of claims 1-5, wherein the dosage form of the drug is an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form.

7. Use according to any one of claims 1 to 6, characterized in that, The dosage form of the drug is tablets, hard capsules, soft capsules, aqueous or oily suspensions, granules, emulsions, syrups, elixirs, injections, or powder injections.

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