Use of shouhui tonifying capsule

Abstract

The application belongs to the field of traditional Chinese medicines, and relates to a new application of Shouhui Tongbian capsules, in particular to an application of the Shouhui Tongbian capsules in a medicine for treating ureteral reflux. It is proved by a pharmacodynamic test that the traditional Chinese medicine composition can enhance the tension and activity of ureter and ileum smooth muscles, has a very important role in relieving ureter smooth muscle spasm and expanding ureter lumen, is beneficial to the transportation of urine, has a significant anti-ureteral reflux effect, is high in safety, and has a broad application prospect and positive clinical significance.

Description

TECHNICAL FIELD

[0001] The present application relates to the use of a traditional Chinese medicine composition, belonging to the field of traditional Chinese medicine. It relates to a new use of Shouhui Tongbian Capsules, in particular to the use of Shouhui Tongbian Capsules in the treatment of ureteral reflux. BACKGROUND

[0002] Bladder cancer (BCa) is the ninth most common cancer worldwide and the thirteenth most common cause of death, ranking seventh in male malignancies and eighteenth in female malignancies.

[0003] Radical cystectomy (RC) plus urinary diversion (UD) is the standard treatment for high-risk non-muscle-invasive bladder cancer and organ-confined muscle-invasive bladder cancer. The probability of postoperative complications after radical cystectomy plus urinary diversion is 25%. Postoperative complications are mainly divided into early complications and late complications. Early complications mainly include postoperative hemorrhage, incision infection, intra-abdominal infection, urinary tract infection, urinary leakage, intestinal leakage, intestinal obstruction, urinary tract reflux, urinary incontinence, etc. Most of the late complications are due to infectious, obstructive factors and tumor recurrence. The common late complications and the corresponding incidence rates are renal function or morphological changes (27%), stoma complications (24%), ureteral ileal anastomosis complications (14%) and urolithiasis (9%).

[0004] Vesicoureteral reflux (VUR) is the reflux of urine from the bladder to the ureter and renal pelvis during urination. Reflux nephropathy (RN) is a syndrome caused by VUR and intrarenal reflux (IRR) with repeated urinary tract infections, leading to scarring, atrophy and abnormal renal function of the kidney, which can cause problems such as urinary tract infection, and if not treated and corrected in time, can progress to chronic renal failure. Generally speaking, smooth muscle contraction is divided into tonic contraction and phasic contraction, and tonic contraction plays a very important role in maintaining the pressure in the lumen (such as blood pressure), and phasic contraction is crucial for pushing the material in the lumen (blood, urine) to the distal end. Ureteral smooth muscle tone mainly refers to the smooth muscle tone of the ureter during tonic contraction. Reducing the tone of the ureteral smooth muscle plays a very important role in relieving ureteral smooth muscle spasm and expanding the ureteral lumen. Therapeutic drugs include antibiotics, anticholinergic drugs, alpha receptor blockers, etc. The clinical commonly used M choline receptor blockers (atropine), calcium antagonists (nimodipine) and other drugs to relax the ureteral smooth muscle, but are limited by the effects on the cardiovascular system and other side effects.

[0005] Chinese patent CN100453105C discloses a composition with the functions of defecation and detoxification, weight loss and lipid reduction, and a preparation method thereof, which has been approved for production and the product is Shouhui Defecation Capsule. The product is a compound traditional Chinese medicine preparation prepared from eight traditional Chinese medicines, i.e. Radix Polygoni Multiflori, Aloe, Cassia Seed, Fructus Lycii, Colla Corii Asini, Radix Ginseng, Rhizoma Atractylodis Macrocephalae and Fructus Aurantii, and can be used for the targeted treatment of functional constipation. The prescription of Shouhui Defecation Capsule is a clinical experience prescription of a famous traditional Chinese medicine doctor. According to the theory of traditional Chinese medicine, the prescription is prepared by combining the products for moistening the intestines, defecation, purging toxin, blood tonifying and dryness moistening, and the products for qi tonifying and spleen invigorating, so that the drugs for descending turbid and eliminating mass are used, the tonification and purgation are combined, the defecation is used for the purpose of defecation, the descending is combined with the ascending, the purgation is combined with the tonification, the quick and slow are combined, the mutual restriction and mutual use are combined, the tonification does not cause stagnation, and the purgation does not harm the healthy qi. Thus, the whole prescription acts on the spleen and stomach, and the spleen and stomach in the middle warmer recover the normal functions of ascending clear and descending turbid. Shouhui Defecation Capsule has a definite curative effect and a quick onset, and has a good therapeutic effect on constipation caused by the internal retention of toxin and the deficiency of yin fluid.

[0006] At present, there is no research or report on Shouhui Defecation Capsule in the aspect of antiureteral reflux. In recent years, with the in-depth development of the research on traditional Chinese medicine preparations, more and more new functions of Shouhui Defecation Capsule have been explored. SUMMARY

[0007] The prescription patent of Shouhui Defecation Capsule product is CN100453105C, and the invention title is “a composition with the functions of defecation and detoxification, weight loss and lipid reduction and a preparation method thereof”, which has been authorized. The technical problem to be solved by the present application is to develop a new use of the marketed product “Shouhui Defecation Capsule” on the basis of Chinese patent CN100453105C. The product is applied to the preparation of drugs for treating vesicoureteral reflux. The use described in the present application is discovered in the process of clinical application of the drug of the company, and is confirmed by relevant pharmacodynamic tests, and has great commercial value.

[0008] The technical problem to be solved by the present application is to develop a new use of the marketed product “Shouhui Defecation Capsule” on the basis of Chinese patent CN100453105C. The product is applied to the preparation of drugs for treating vesicoureteral reflux. The use described in the present application is discovered in the process of clinical application of the drug of the company, and is confirmed by relevant pharmacodynamic tests, and has great commercial value.

[0009] The traditional Chinese medicine composition in the present application is prepared from Radix Polygoni Multiflori, Aloe, Cassia Seed, Fructus Lycii, Colla Corii Asini, Radix Ginseng, Rhizoma Atractylodis Macrocephalae and Fructus Aurantii.

[0010] The traditional Chinese medicine composition in the present application is applied to the preparation of drugs for treating vesicoureteral reflux.

[0011] In some embodiments, the ureteral reflux is primary vesicoureteral reflux and postoperative ureteral reflux in reconstructed bladder.

[0012] The components are as follows in terms of weight parts: 60-150 parts of Radix Polygoni Multiflori, 100-200 parts of Aloe, 80-180 parts of Cassia Seed, 30-150 parts of Fructus Lycii, 30-150 parts of Colla Corii Asini, 20-100 parts of Radix Ginseng, 20-100 parts of Atractylodes Macrocephala Koidz, and 50-200 parts of Fructus Aurantii.

[0013] In some embodiments, the components are as follows in terms of weight parts: 120 parts of Radix Polygoni Multiflori, 160 parts of Aloe, 140 parts of Cassia Seed, 75 parts of Fructus Lycii, 75 parts of Colla Corii Asini, 50 parts of Radix Ginseng, 50 parts of Atractylodes Macrocephala Koidz, and 120 parts of Fructus Aurantii.

[0014] The preparation method of the traditional Chinese medicine composition in the present application comprises the following steps: (1) grinding and sieving Colla Corii Asini and Radix Ginseng to obtain fine powder, for standby use;

[0015] (2) weighing Fructus Lycii, Atractylodes Macrocephala Koidz, and Fructus Aurantii according to the proportion, soaking, boiling, filtering, and concentrating to obtain concentrated liquid;

[0016] (3) weighing Radix Polygoni Multiflori, Cassia Seed, and Aloe according to the proportion, removing impurities, washing, drying, grinding, and sieving to obtain fine powder;

[0017] (4) combining the fine powder obtained in step (1) and the concentrated liquid obtained in step (2), mixing uniformly, concentrating into thick paste, adjusting the pH value to 5.5-6.5, drying under reduced pressure, and crushing and sieving to mix with the fine powder in step (3) to obtain the traditional Chinese medicine composition.

[0018] The traditional Chinese medicine composition provided in the present application can further contain pharmaceutically acceptable excipients.

[0019] In some embodiments, the traditional Chinese medicine composition is prepared with pharmaceutically acceptable excipients at a weight ratio of 1:1.5-8.5.

[0020] The traditional Chinese medicine composition provided in the present application can be further prepared into a clinically acceptable dosage form.

[0021] In some embodiments, the dosage form is tablet, granule, capsule, mixture, pill, dripping pill, solid dispersion, or microcapsule.

[0022] In more preferred embodiments, the dosage form is capsule.

[0023] In the present application, the pharmaceutically acceptable excipients include fillers and binders, the fillers are one or more of mannitol, lactose, sorbitol, sucrose, and cyclodextrin, and the binders are one or more of 3% PVP in 75% ethanol solution, 3% hydroxypropyl methylcellulose in 50% ethanol solution, 10% povidone K30 in water solution, and 30% starch paste.

[0024] In some embodiments, the filler is a mixture of cyclodextrin and sorbitol, and the ratio of cyclodextrin to sorbitol is 1:0.5-1.5 by weight.

[0025] In more preferred embodiments, the cyclodextrin is hydroxypropyl-β-cyclodextrin.

[0026] The traditional Chinese medicine preparation described in the present application is Shouhui Tongbian Capsules.

[0027] The present application achieves the following technical effects:

[0028] Shouhui Tongbian Capsules have a contractile effect on the isolated ureter smooth muscle of normal rabbits, can dilate the ureter lumen, and is beneficial for the transportation of urine. In the isolated ileum contraction verification experiment on guinea pigs, Shouhui Tongbian Capsules can increase the tension of the ileum and enhance the contraction of smooth muscle, indicating that Shouhui Tongbian Capsules have a certain anti-ureteral reflux effect.

[0029] To verify the anti-ureteral reflux effect of the traditional Chinese medicine composition of the present application, the inventors have carried out pharmacodynamic test research and drug clinical research. It should be noted that the drugs selected for the pharmacodynamic test and clinical research of the present application are drugs obtained by the representative formula and preparation method of the present application. The tests and results of other formulas and drugs obtained by the preparation method included in the present application are not listed one by one due to space limitations. Specific embodiments

[0030] The present application will be further described in detail below in conjunction with specific embodiments, but the embodiments of the present application are not limited by the following examples. Any further changes, modifications, substitutions, combinations, and simplifications made on the basis of the essence of the present application shall be considered equivalent replacements and included within the scope of protection of the present application.

[0031] Pharmacodynamic test examples

[0032] Example 1 Experimental study on the effect of Shouhui Tongbian Capsule-containing serum on isolated ureter smooth muscle of rabbits

[0033] 1. Experimental materials

[0034] 1.1 Experimental animals

[0035] 110 clean grade white rabbits, 6-8 months old, half male and half female, weighing 2-2.5 kg, 40 for drug-containing serum preparation, 70 for experimental specimen preparation, provided by Lunan Pharmaceutical Group Co., Ltd. License No.: SYXK(Lu)20230023.

[0036] 1.2 Experimental drugs and reagents

[0037] Chouhao Capsule (Lu'nan Houpu Pharmaceutical Co., Ltd., State Drug Approval Code Z20150041), phentolamine 2 x 10 - 6 mol / L, atropine 2 x 10 -5 mol / L.

[0038] Preparation of Krebs' solution: 1000 mL of Krebs' solution contains NaCl 6.9 g, 10% KCl 3.0 mL (0.35 g), 10% MgSO4·7H2O 2.9 mL (0.29 g), 10% KH2PO4 1.6 mL (0.16 g), NaHCO3 2.1 g, CaCl2 0.28 g, glucose 2.0 g. Prepare 1000 mL of Krebs' solution and store it in a refrigerator at 4℃ for standby.

[0039] 2 Experimental method

[0040] In this experiment, the effects of different concentrations of Chouhao Capsule serum on the isolated ureter smooth muscle of normal rabbits were studied by serum pharmacology method, and the effects of different concentrations of Chouhao Capsule serum on the isolated specimens were observed.

[0041] 2.1 Preparation of drug-containing serum

[0042] Randomly divided into blank serum group, Chouhao Capsule low (L), medium (M), high (H) concentration group. After 12 h fasting, the blank serum group was given the same amount of normal saline by gavage, and the low, medium and high concentration groups were given Chouhao Capsule by gavage at the concentrations of 0.048 g / kg, 0.096 g / kg and 0.192 g / kg, respectively, 2 times / d, for a total of 3 d. 1 h after the last gavage (12 h fasting before gavage, but not water fasting), the blood was taken from the carotid artery and centrifuged at 3000 r / min for 10 min. The upper serum was labeled and stored at -20℃ for standby.

[0043] 2.2 Preparation of experimental specimens

[0044] Hit the back of the rabbit's head with a blunt wooden stick, quickly open the abdomen, take out the ureter, and immediately put it in a glass dish containing Krebs' solution, and inhale 95% O2+5% CO2 mixed gas, carefully remove the surrounding fat and connective tissue, and prepare about 1 cm of ureter segment.

[0045] 2.3 Group experiment

[0046] The ureter segment was hung in the constant temperature smooth muscle bath containing the Kreb's solution ([38.5±0.5)℃, pH=7.4], mixed gas containing 95% O2 and 5% CO2 was inhaled, the sample was given a basic tension of 2g, and was stabilized for 60 min (liquid was changed every 15 min), the contraction of the sample was recorded by the Powerlab biological function signal acquisition and processing system controlled by the computer, the contraction frequency (times / 10 min), strength (g), and activity ([g·times) / 10 min activity=strength×frequency] of the sample were observed. After each experiment, the sample was washed with the Kreb's solution for 3 times, the tension of the sample was recovered to the baseline, and the next experiment was performed.

[0047] 2.4 Statistical processing method

[0048] The data results were represented by mean±standard deviation (X±S), the analysis software was SPSS 16.0 statistical software package, one-way analysis of variance was used for comparison of data between groups, and P<0.05 was considered as significant difference.

[0049] 3 Experimental results

[0050] 3.1 The effect of 1 mL of different concentrations of Shoujiaotongbian capsule drug-containing serum on the isolated ureter smooth muscle of rabbits, and the results are shown in Table 1.

[0051] As shown in Table 1, the blank serum group and the different concentrations of Shoujiaotongbian capsule serum group can enhance the tension and activity of the isolated ureter smooth muscle of normal rabbits, and compared with the blank control group, there is significant difference (P<0.05).

[0052] Table 1 The effect of different concentrations of Shoujiaotongbian serum group on the isolated ureter smooth muscle of rabbits

[0053] Group n Tension (g) Frequency (times / 10 min) Motility [g·times) / 10 min] Control group 10 2.17±0.47 32.15±5.45 69.77±10.34 Blank serum group 10 2.36±0.33* 35.33±5.16 83.38±11.68* Chouhoutongjian capsule (L) 10 2.77±0.28** 38.67±3.64 107.12±12.41** Chouhoutongjian capsule (M) 10 2.81±0.23** 39.02±2.72 109.64±9.76** Chouhoutongjian capsule (H) 10 2.94±0.31** 39.74±3.44 116.84±8.66**

[0054] Note: compared with the blank control group, *P<0.05, **P<0.01.

[0055] 3.2 The effect of blocking agent plus middle concentration of Shoujiaotongbian capsule serum on the isolated ureter smooth muscle of rabbits, and the results are shown in Table 2.

[0056] As shown in the results, atropine and phentolamine can block the contraction effect of middle concentration of Shoujiaotongbian capsule serum on the ureter smooth muscle (P<0.05).

[0057] Table 2 The effect of blocking agent plus middle concentration of serum group on the isolated ureter smooth muscle of rabbits

[0058] Group n Tension (g) Frequency (times / 10 min) Motility [g·times) / 10 min] Chouhoutongjian capsule (M) 10 2.81±0.23 39.02±2.72 109.64±9.76 Atropine + serum group 10 2.54±0.21* 37.41±4.42 95.02±7.26* Phentolamine + serum group 10 2.47±0.36* 35.67±3.35 88.10±8.34*

[0059] According to the results of the experiment, the blank serum group and the different concentrations of Shouhao Capsules group have contraction effect on the isolated ureter smooth muscle of normal rabbits, which is beneficial to the transportation of urine. At the same time, it is found that atropine group and phentolamine group can block the contraction effect of medium concentration Shouhao Capsules serum on ureter smooth muscle, which has significant difference. Therefore, Shouhao Capsules can expand the ureter lumen, which is beneficial to the transportation of urine, and has certain anti-ureteral reflux effect. Example 2 Experimental study on the contraction effect of Shouhao Capsules on guinea pig ileum

[0060] 1. Experimental materials

[0061] 1.1 Experimental animals

[0062] 50 clean grade guinea pigs, male, weighing 300±50g, were raised in an environment with a temperature of 20-25℃ and a relative humidity of 40%-70%, and were provided by Lunan Pharmaceutical Group Co., Ltd. The qualified certificate number is SYXK(Lu)20230023.

[0063] 1.2 Experimental drugs and reagents

[0064] Shouhao Capsules (Lunan Hupu Pharmaceutical Co., Ltd., National Drug Standard Z20150041), histamine dihydrochloride (Suzhou Zhonghua Pharmaceutical Industry Co., Ltd., batch number: H20030447, specification: 10mg / tablet)

[0065] Preparation of Krebs solution: according to 1000mL of Kerbs solution containing NaCl 6.9g, 10% KCl 3.0mL (0.35g), 10% MgSO4·7H2O 2.9mL (0.29g), 10% KH2PO41.6mL (0.16g), NaHCO32.1g, CaCl20.28g, glucose 2.0g, prepare Kerbs solution 1000mL, store in 4℃ refrigerator for standby.

[0066] 2 Experimental method

[0067] In this experiment, Shouhao Capsules preparation was taken as a representative, and the effect of different concentrations of Shouhao Capsules on its contraction was observed by isolated ileum experiment.

[0068] 2.1 Grouping

[0069] 50 guinea pigs were randomly divided into 5 groups, 10 in each group. They were blank group, positive control group: histamine dihydrochloride group, Shouhao Capsules low (L), medium (M) and high (H) concentration groups.

[0070] 2.2 Preparation of experimental specimens

[0071] The guinea pigs were fasted for 24 hours before the experiment and allowed to drink water freely. The guinea pigs were killed by hitting their heads and immediately dissected to find the ileum. The ileum was cut 1 cm from the ileocecal junction and a 10 cm section was removed and placed in a Petri dish containing Tyrode's solution aerated with air. The mesentery was removed and the contents of the ileum were washed out with Tyrode's solution using a syringe. The ileum was then cut into several small sections (1-1.5 cm each) and placed in fresh Tyrode's solution. Care was taken not to stretch the ileum during the procedure to avoid affecting the contractile function.

[0072] 2.3 Observation of the contraction of the isolated ileum

[0073] A small section of the ileum was placed in a Petri dish containing Krebs' solution and one end of the ileum was attached to a wire connected to a gas bellows. The Petri dish was then placed in a 37°C water bath. The outflow tube from the gas bellows was connected to a screw clamp and the rate of air flow was adjusted so that the air bubbles in the water bath were just escaping one at a time. The other end of the ileum was attached to a force transducer and connected to a computer interface. The baseline was set to 1 g and the ileum was allowed to stabilize for 10-30 minutes. After recording a normal contraction curve, the drugs were added to the water bath one at a time and the changes in tension of the ileum were recorded using the Powerlab biological signal acquisition and analysis system. After 3 minutes of contact with the test drug, the amplitude of the contraction was observed and the ileum was then washed twice with Tyrode's solution until the baseline returned to the level before the addition of the drug. A second baseline was then recorded and a second test drug was added. The volume of the solution in the water bath was the same for each test.

[0074] The experiment was divided into 5 groups: a blank group (normal saline), a positive control group (0.01% histamine 0.1 mL), and low (L), medium (M) and high (H) concentration groups of Shouhoutongjian capsules (0.06 g / kg, 0.12 g / kg and 0.24 g / kg, respectively). The drugs were added to the water bath and the contraction of the ileum was observed. The tension of the ileum was recorded and each group was repeated 6 times.

[0075] 2.4 Statistical processing method

[0076] The data were expressed as the mean ± standard deviation (X ± S) and analyzed using SPSS 16.0 statistical software package. One-way ANOVA was used to compare the data between groups and P<0.05 was considered to be significantly different.

[0077] 3 Experimental results

[0078] The effects of Shouhoutongjian capsules at different concentrations on the contraction tension of the isolated ileum of guinea pigs are shown in Table 3.

[0079] The ileum of the guinea pigs in the blank group showed rhythmic contractions. After the administration of histamine in the positive control group, the ileum smooth muscle produced a persistent spastic phase contraction. The contraction of the isolated ileum caused by Shouhoutongjian capsules was significantly different from that of the blank group (P<0.05) and the difference was more significant as the concentration increased.

[0080] Table 3 Changes of tension of isolated ileum of guinea pigs

[0081] Group n Guinea pig ileum contraction tension (g) Control group 6 0.507±0.043 Histamine group 6 2.179±0.079** Chouhoutongjian capsule (L) 6 1.436±0.057* Chouhoutongjian capsule (M) 6 1.652±0.064** Chouhoutongjian capsule (M) 6 2.281±0.043**

[0082] Note: compared with the blank control group, *P<0.05, **P<0.01.

[0083] The guinea pig ileum is rich in histamine receptors. Histamine can bind to H1 histamine receptors on the mucosa of the ileum, causing smooth muscle excitation, ileum contraction and spasm. Under the action of histamine, the contraction of the smooth muscle of the guinea pig ileum is enhanced, and the contraction amplitude increases rapidly. The first capsule can produce the phenomenon of increased tension of the ileum and enhanced contraction of the smooth muscle of the isolated ileum of guinea pigs, and there is a significant difference compared with the blank control group, and the effect is equivalent to that of histamine.

Claims

1. Use of a traditional Chinese medicine composition in the preparation of a medicament for treating vesicoureteral reflux, characterized in that, The traditional Chinese medicine composition comprises, by weight, 60-150 parts of Radix Polygoni Multiflori, 100-200 parts of Aloe, 80-180 parts of Cassia Seed, 30-150 parts of Fructus Lycii, 30-150 parts of Colla Corii Asini, 20-100 parts of Radix Ginseng, 20-100 parts of Atractylodes, and 50-200 parts of Fructus Aurantii.

2. Use according to claim 1, characterized in that, The traditional Chinese medicine composition comprises, by weight, 120 parts of Radix Polygoni Multiflori, 160 parts of Aloe, 140 parts of Cassia Seed, 75 parts of Fructus Lycii, 75 parts of Colla Corii Asini, 50 parts of Radix Ginseng, 50 parts of Atractylodes, and 120 parts of Fructus Aurantii.

3. Use according to any one of claims 1-2, characterized in that, The preparation method of the traditional Chinese medicine composition comprises the following steps: (1) grinding and sieving Colla Corii Asini and Radix Ginseng to obtain fine powder, for standby use; (2) soaking, boiling and filtering Fructus Lycii, Atractylodes and Fructus Aurantii in water according to the proportion, and concentrating to obtain concentrated liquid; (3) removing impurities, washing and drying Radix Polygoni Multiflori, Cassia Seed and Aloe, grinding and sieving to obtain fine powder; (4) mixing the fine powder obtained in step (1) and the concentrated liquid obtained in step (2), uniformly mixing, concentrating to obtain thick paste, adjusting pH value to 5.5-6.5, drying under reduced pressure, grinding and sieving, and mixing with the fine powder in step (3) to obtain the traditional Chinese medicine composition.

4. The use according to claim 1, characterized in that, The ureteral reflux is primary vesicoureteral reflux and postoperative vesicoureteral reflux.