A pharmaceutical composition for treating autosomal dominant polycystic kidney disease and a preparation method thereof

Abstract

The present invention belongs to the field of pharmaceutical technology. The present invention provides a pharmaceutical composition for treating autosomal dominant polycystic kidney disease, and the pharmaceutical composition comprises valtrate E and morindaoigosaccharides. The obtained pharmaceutical composition of the present invention can significantly inhibit the growth of vesicles and significantly down-regulate the expression of MPO, Ki67 and ISL1 proteins, and can be used for the treatment of autosomal dominant polycystic kidney disease.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceuticals, and particularly relates to a pharmaceutical composition for treating autosomal dominant polycystic kidney disease and a preparation method thereof. Background Art

[0002] Autosomal dominant polycystic kidney disease is mainly characterized by progressive cyst growth in both kidneys, which can affect multiple systems, including liver, pancreas, and arachnoid cysts, etc., causing irreversible damage to the structure and function of the kidneys. The clinical manifestations of this disease are highly heterogeneous, with complex genetic factors, and there are few effective diagnostic and treatment measures. Usually, kidney transplantation and dialysis are used, and tolvaptan is the only clinically approved drug. Therefore, for this disease, it is very important to study more treatment methods and drugs.

[0003] Currently, through continuous exploration, people have studied the effects of various drugs or natural active substances in the treatment of autosomal dominant polycystic kidney disease. For example, Qiu Zhiwei studied the effect of obacunone on inhibiting the occurrence of renal cysts in polycystic kidney disease (Qiu Zhiwei. Pharmacological study on the inhibition of the occurrence and development of renal cysts in polycystic kidney disease by obacunone [D]. Peking University Health Science Center, 2022.); Li Qinggang et al. studied the application of GNE-495 in the preparation of drugs for treating autosomal dominant polycystic kidney disease in CN117797148A; Yang Baoxue et al. studied the application of ethyl ganoderate C2 in the preparation of products for treating and / or preventing autosomal dominant polycystic kidney disease in CN106924301A.

[0004] However, in the prior art, the research on drugs for treating autosomal dominant polycystic kidney disease is still in the initial exploration stage, the effective substances found are relatively few, and there is no effective theory to follow. Therefore, it is urgently needed in this field to study more drugs or pharmaceutical compositions effective in treating autosomal dominant polycystic kidney disease. Summary of the Invention

[0005] Aiming at the defects of the prior art, the purpose of the present invention is to provide a new pharmaceutical composition for treating autosomal dominant polycystic kidney disease. This pharmaceutical composition can inhibit the growth of cysts and the expression of related proteins.

[0006] In order to achieve the above purpose, the technical solution provided by the present invention is as follows:

[0007] A pharmaceutical composition for treating autosomal dominant polycystic kidney disease, the pharmaceutical composition comprising valtrate E and morindaoigosaccharides.

[0008] Preferably, the pharmaceutical composition consists of valtrate E and morindaoigosaccharides, and the weight ratio of valtrate E to morindaoigosaccharides is 1-3:1.

[0009] More preferably, the weight ratio of valtrate E to morindaoigosaccharides is 3:1.

[0010] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, and the preparation method includes mixing valtrate E and morindaoigosaccharides.

[0011] Preferably, the preparation method includes: preparing a mother liquor of valtrate E with DMSO, and then diluting it with physiological saline to obtain a primary solution of valtrate E; adding morindaoigosaccharides to physiological saline, and then adding the primary solution of valtrate E so that valtrate E and morindaoigosaccharides reach the above-mentioned weight ratio, and completing the preparation of the pharmaceutical composition solution.

[0012] More preferably, when preparing the pharmaceutical composition solution, the content of DMSO in the pharmaceutical composition solution is not higher than 0.07%.

[0013] Valtrate E is one of the active components in Valeriana jatamansi Jones, and currently it is found to have anti-inflammatory effects. At the same time, it is also found that it has a certain inhibitory effect on tumor cells (Lan Ming. Effects of valtrate E on the proliferation, invasion and migration of human hepatocellular carcinoma HepG2 cells [D]. Southwest Jiaotong University, 2015.). However, in addition to this, people have not found other medical uses for it. As shown in the relevant experimental examples of the present invention, when valtrate E is used alone, it cannot inhibit the growth of vesicles, but instead slightly promotes the growth of vesicles. The inventor found through exploration that when valtrate E is combined with morindaoigosaccharides, the growth of vesicles can be significantly inhibited, indicating that morindaoigosaccharides and valtrate E have good synergistic effects in inhibiting the growth of vesicles.

[0014] Morindaoigosaccharides are mainly used to treat depression, insomnia, anxiety, decreased libido, tinnitus and amnesia, etc. Although researchers have conducted a lot of research on combining it with other drugs, for example, Shao Min et al. studied the clinical effect of combining morindaoigosaccharides with paroxetine in the treatment of depression (Shao Min, Zhang Jun, Qian Xiaoping. Observation on the clinical effect of morindaoigosaccharides combined with paroxetine in the treatment of depression [J]. China Medical Innovation, 2022, 19(28): 52-55.), but no one has combined morindaoigosaccharides with other substances to investigate its therapeutic effect on autosomal dominant polycystic kidney disease. As shown in the relevant experimental examples of the present invention, using only morindaoigosaccharides alone also cannot inhibit the growth of vesicles. As shown in the experimental examples of the present invention, when morindaoigosaccharides and valtrate E are used in combination, within a relatively wide dosage range, the expressions of MPO, Ki67 and ISL1 proteins are all significantly down-regulated, indicating that the effect of this drug combination in inhibiting the growth of vesicles may be due to the down-regulation of related proteins.

[0015] Advantages of the present invention:

[0016] The drug composition obtained by the present invention can significantly inhibit the growth of cysts and significantly down-regulate the expression of MPO, Ki67, and ISL1 proteins, and can be used for the treatment of autosomal dominant polycystic kidney disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a graph showing the experimental results of the drug composition in Example 1 of the present invention in inhibiting cyst growth;

[0018] Figure 2 It is a graph showing the experimental results of different dosages of the drug composition of the present invention in inhibiting cyst growth;

[0019] Figure 3 It is a graph showing the experimental results of using only valerianin E or morindao ligosaccharides in affecting cyst growth. DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention will be specifically described below through examples. It is necessary to point out here that the following examples are only used to further illustrate the present invention and cannot be construed as limiting the protection scope of the present invention. Some non-essential improvements and adjustments made by those skilled in the art based on the above-mentioned invention content still fall within the protection scope of the present invention.

[0021] Example 1

[0022] Prepare 20 mg of valerianin E, dissolve it in 1 mL of DMSO to obtain a valerianin E stock solution. When in use, dilute it with physiological saline (ultrasonic dispersion to be uniform) and use it immediately after preparation. Prepare 20 mg of morindao ligosaccharides and dissolve it in physiological saline. Mix the valerianin E and morindao ligosaccharides solutions so that the concentrations of valerianin E and morindao ligosaccharides are 7.5 μg / mL and 2.5 μg / mL respectively, and at the same time ensure that the content of DMSO is not higher than 0.07%.

[0023] Example 2

[0024] Prepare 20 mg of valerianin E, dissolve it in 1 mL of DMSO to obtain a valerianin E stock solution. When in use, dilute it with physiological saline (ultrasonic dispersion to be uniform) and use it immediately after preparation. Prepare 20 mg of morindao ligosaccharides and dissolve it in physiological saline. Mix the valerianin E and morindao ligosaccharides solutions so that the concentrations of valerianin E and morindao ligosaccharides are 5.0 μg / mL and 2.5 μg / mL respectively, and at the same time ensure that the content of DMSO is not higher than 0.07%.

[0025] Example 3

[0026] Prepare 20 mg of valeriana jatamansi Jones extract E, dissolve it in 1 mL of DMSO to obtain the stock solution of valeriana jatamansi Jones extract E. When in use, dilute it with normal saline (disperse evenly by ultrasonic wave) and use it freshly prepared. Prepare 20 mg of morindaofficinalis How oligosaccharides and dissolve them with normal saline. Mix the valeriana jatamansi Jones extract E with the morindaofficinalis How oligosaccharide solution so that the concentrations of valeriana jatamansi Jones extract E and morindaofficinalis How oligosaccharides are 2.5 μg / mL and 2.5 μg / mL respectively, and at the same time ensure that the content of DMSO is not higher than 0.07%.

[0027] Experimental Example 1

[0028] Aspirate the Matrigel, place MDCK cells into the Matrigel, and add 20 μmol / L of forskolin (MedChemExpress, USA) to stimulate the formation of round vesicles as the control group. When adding forskolin, add the drug composition of Example 1 so that the content of the drug composition is 450 μg / L for co-culture as the experimental group. Continue to culture the experimental group and the control group. On the 4th, 8th, and 12th days, measure the diameter of the cultured vesicles. It is found through the experiment that the diameter of the vesicles measured in the experimental group is significantly lower than that in the control group during the investigation period from the 4th day to the 12th day, indicating that the experimental group has an inhibitory effect on the growth of vesicles. The specific results are as Figure 1 shown.

[0029] Experimental Example 2

[0030] On the basis of Experimental Example 1, investigate the effects of adding different amounts of the drug composition of Example 1 on the vesicles. The added amounts of the drug composition investigated in this experimental example are 300 μg / L, 600 μg / L, and 750 μg / L respectively. As Figure 2 shown, within the added amount range of 300 μg / L to 750 μg / L, there is an obvious inhibitory effect on the growth of vesicles.

[0031] Experimental Example 3

[0032] On the basis of Experimental Example 1, this experimental example investigates the effects of adding only valeriana jatamansi Jones extract E (content is 450 μg / L) and only morindaofficinalis How oligosaccharides (content is 450 μg / L) on the growth of vesicles. As Figure 3 shown, whether adding only valeriana jatamansi Jones extract E or only morindaofficinalis How oligosaccharides, there is no inhibitory effect on the growth of vesicles. Even when adding only valeriana jatamansi Jones extract E, there is a slight promoting effect on the growth of vesicles. This indicates that valeriana jatamansi Jones extract E and morindaofficinalis How oligosaccharides have a synergistic effect in inhibiting the growth of vesicles and neither of them can be absent.

[0033] On the basis of Experimental Example 1, the ratios of valeriana jatamansi Jones extract E and morindao ligosaccharides were adjusted, and the ratios of Example 2 and Example 3 were used respectively to conduct the same experiment. It was found that the composition of Example 2 could still significantly inhibit the growth of vesicles, and the vesicle diameters on the 12th day were more than 30% smaller than those of the control group.

[0034] Experimental Example 4

[0035] Using the model (NM-KO200652) constructed by Model Animal Research Center of Shanghai Institutes for Biological Sciences as the experimental mice. On the 4th day after the onset of the experimental mice, normal saline and the pharmaceutical composition of Example 1 (100 mg / kg, 200 mg / kg, and 300 mg / kg) were administered respectively for 3 consecutive days. On the 10th day, the kidneys were taken for immunohistochemical staining to detect the number of positively expressed cells of MPO, Ki67, and ISL1 proteins. As shown in Table 1, when the dosage was 100 mg / kg to 300 mg / kg, the expressions of MPO, Ki67, and ISL1 proteins could be significantly down-regulated.

[0036] Table 1

[0037]

[0038]

Claims

1. A pharmaceutical composition for treating autosomal dominant polycystic kidney disease, characterized in that: The pharmaceutical composition consists of spider incense E and Morinda officinalis oligosaccharides, and the weight ratio of the spider incense E to the Morinda officinalis oligosaccharides is 1-3:

1.

2. A pharmaceutical composition for treating autosomal dominant polycystic kidney disease according to claim 1, characterized in that: The weight ratio of the spider fragrance E to Morinda officinalis oligosaccharide is 3:

1.

3. A method for preparing a pharmaceutical composition for treating autosomal dominant polycystic kidney disease, characterized in that: The pharmaceutical composition for treating autosomal dominant polycystic kidney disease is the composition according to claim 1 or 2; the preparation method comprises mixing the spider incense E and Morinda officinalis oligosaccharides.

4. The preparation method according to claim 3, characterized in that: The preparation method comprises: preparing spider odorant E into a mother solution with DMSO, and then diluting it with physiological saline to obtain a spider odorant E initial solution; adding Morinda officinalis oligosaccharides into the physiological saline, and then adding the spider odorant E initial solution, so that the spider odorant E and Morinda officinalis oligosaccharides reach the weight ratio, and the preparation of the pharmaceutical composition solution is completed.

5. The preparation method according to claim 4, characterized in that: When preparing the pharmaceutical composition solution, the content of DMSO in the pharmaceutical composition solution is not higher than 0.07%.

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