Application of polaprezinc in preparation of medicine for relieving gastrointestinal toxicity caused by chemotherapy

Abstract

The invention discloses application of polaprezinc in preparation of a medicine for relieving gastrointestinal toxicity caused by chemotherapy, and belongs to the technical field of medicine. Polaprezinc is provided for relieving gastrointestinal toxicity caused by irinotecan for the first time, can effectively improve mouse small intestine length shortening caused by irinotecan, meanwhile can reduce intestinal inflammation and relieve mouse ileum injury caused by irinotecan, effectively improves the intestinal barrier function of mice, and can be used for preparing medicines for preventing and treating irinotecan. According to the present invention, the compound has the significant alleviation effect on the intestinal toxicity caused by irinotecan, can be used for preparing the drug for alleviating the gastrointestinal toxicity caused by chemotherapy, and is expected to alleviate the chemotherapy-related gastrointestinal toxicity by combining the application of polaprezinc for intervention in the tumor chemotherapy process, such that the new drug choice is provided for the clinical alleviation of the chemotherapy-induced intestinal adverse reaction.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and specifically relates to the application of polyprene zinc in the preparation of drugs for alleviating gastrointestinal toxicity caused by chemotherapy. Background Art

[0002] Irinotecan is a semi-synthetic derivative of camptothecin, which can inhibit topoisomerase I and interfere with DNA replication, effectively preventing tumor cell proliferation. It is mainly used to treat metastatic colorectal cancer, and is also widely used in the treatment of solid tumors such as lung cancer, breast cancer, gastric cancer, and ovarian cancer. However, it is also accompanied by strong toxic side effects. Studies have shown that about 20% of patients will experience severe gastrointestinal adverse reactions when receiving irinotecan-based combination chemotherapy regimens. This toxic reaction is mainly caused by intestinal mucosal damage. It is currently believed that it is closely related to intestinal flora disorders and bacterial β-glucuronidase-mediated metabolite SN-38 reactivation. In order to alleviate the intestinal toxic side effects caused by irinotecan, existing intervention methods include β-glucuronidase inhibitors and antibiotics, but these methods also have side effects, such as antibiotics' non-selective killing of intestinal flora leading to an imbalance in the intestinal flora ecology. Therefore, the present invention aims to develop a new drug or combination therapy to alleviate irinotecan-related intestinal toxicity, provide patients with a safer and more effective treatment regimen, and promote the wider application of irinotecan in tumor treatment.

[0003] Polaprezinc is a chelate of zinc (Zn) and L-carnosine, which can increase the expression of heat shock proteins, achieve antioxidant and anti-apoptotic effects to protect the gastric mucosa, and serve as a new generation of gastric mucosal protectants. Research reports show that Polaprezinc can restore the level of glutathione in the mucosa, and continuously downregulate the protein expression of tumor necrosis factor-α, interleukin-1β, macrophage inflammatory protein-2, and cytokine-induced neutrophil chemoattractant factor-2a, all of which are activated in ulcer tissues and promote the healing of ulcer mucosa. In addition, Polaprezinc significantly reduces the area of ​​gastric ulcers in a dose-dependent manner, while reducing the activity of xanthine oxidase and myeloperoxidase, reducing the level of malondialdehyde in the ulcer mucosa, and slowing down drug-related gastric mucosal damage. Summary of the invention

[0004] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a new application of polypregnenol in the preparation of drugs for alleviating gastrointestinal toxicity caused by chemotherapy. The polypregnenol in the present invention can significantly improve the intestinal barrier function of mice caused by irinotecan, and effectively reduce the gastrointestinal toxicity caused by irinotecan.

[0005] Another object of the present invention is to provide a pharmaceutical composition for alleviating gastrointestinal toxicity caused by irinotecan.

[0006] Technical solution: In order to achieve the above technical objectives, the present invention provides the use of polyprene zinc in the preparation of drugs for alleviating gastrointestinal toxicity caused by chemotherapy.

[0007] The invention discloses an application of polyprene zinc or a pharmaceutically acceptable salt thereof in the preparation of a drug for alleviating gastrointestinal toxicity caused by chemotherapy.

[0008] The invention discloses an application of the polyprene zinc or a pharmaceutically acceptable salt thereof in the preparation of a drug for alleviating gastrointestinal toxicity caused by irinotecan.

[0009] Furthermore, the polyprenisin zinc is preferably administered to mammals at a dose of 50-150 mg / kg body weight for use in alleviating gastrointestinal toxicity caused by chemotherapy.

[0010] Preferably, the polyprenatol zinc is administered to mammals at a dose of 100 mg / kg body weight for use as a drug for alleviating gastrointestinal toxicity caused by chemotherapy.

[0011] Among them, the polyprenisin zinc can alleviate intestinal villus damage and thus reduce the gastrointestinal toxicity caused by the chemotherapy drug irinotecan.

[0012] The pharmaceutical composition for alleviating gastrointestinal toxicity caused by irinotecan comprises polyprednisolone zinc as an active ingredient and pharmaceutically acceptable carriers and excipients.

[0013] Furthermore, the auxiliary material comprises one or more of an emulsifier, a lubricant, a solvent, a diluent, a binder, a wetting agent, a preservative, an antioxidant, a solubilizer, and a disintegrant.

[0014] Wherein, the emulsifier is selected from at least one of Tweens, Spans, glycerol fatty acid esters, gelatin, pectin, agar, sodium alginate and silicon dioxide.

[0015] Wherein, the lubricant is selected from at least one of magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycols, and micro-powdered silica gel.

[0016] Wherein, the solvent is selected from at least one of water, oil, ethanol, glycerol, dimethyl sulfoxide, fatty oil, propylene glycol, and polyethylene glycol.

[0017] Wherein, the diluent is selected from at least one of starch, sugar, cellulose and inorganic salts.

[0018] Wherein, the adhesive is selected from at least one of starch slurry, sodium carboxymethyl cellulose, povidone, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose.

[0019] Wherein, the wetting agent is selected from at least one of water and ethanol.

[0020] Wherein, the preservative is selected from at least one of benzoic acid and its salts, sorbic acid and its salts and parabens.

[0021] Wherein, the antioxidant is selected from at least one of ascorbic acid, sulfite, bisulfite, gallic acid and lipids thereof.

[0022] Wherein, the solubilizing agent is selected from at least one of Tweens, polyoxyethylene fatty alcohol ethers, sulfates and sulfonates.

[0023] Wherein, the disintegrant is selected from at least one of starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and cross-linked polyvinyl pyrrolidone.

[0024] The drug dosage form is granules, tablets, capsules, oral liquids, pills, emulsions, suspensions, injections, infusions or sprays.

[0025] Wherein, the administration route of the drug is oral administration, enema administration or injection administration.

[0026] In the experiment of the present invention, the experimental mice were divided into a control group of polyprezinc and a drug administration group. The control group was given normal drinking water, and the polyprezinc drug administration group was given drinking water containing polyprezinc. The irinotecan mouse diarrhea model was constructed. After one week of adaptive feeding, the two groups of mice were given normal drinking water and drinking water containing polyprezinc, respectively; the two groups of mice were intraperitoneally injected with irinotecan (the dosage of mice was 25 mg / kg), and the weight changes, diarrhea and mortality of mice in each group were observed; the remaining mice were killed on the 8th day, and the physiological and biochemical indicators and intestinal damage of the mice were investigated.

[0027] The experimental results of the present invention show that polyprezinc can significantly improve irinotecan-induced intestinal barrier damage in mice and effectively alleviate the intestinal toxicity caused by it. In the polyprezinc intervention group, the pathological score of the mouse ileum decreased significantly, and the villus length and crypt height were significantly restored, indicating that it has a protective effect on the intestinal tissue structure. Therefore, combined with polyprezinc intervention during tumor chemotherapy, it is expected to reduce the intestinal toxicity caused by irinotecan, providing potential application value for the development of new drugs to alleviate chemotherapy-related gastrointestinal toxicity.

[0028] The present invention proposes a new use of polyprezinc in the preparation of drugs for relieving chemotherapy-induced gastrointestinal toxicity. Experiments show that polyprezinc has a significant improvement effect on the intestinal barrier function of mice and can effectively reduce the intestinal toxicity caused by irinotecan. Therefore, the present invention provides a new method for relieving the gastrointestinal toxicity caused by irinotecan clinical treatment by combining polyprezinc in the process of tumor chemotherapy, which provides a new option for the development of drugs for relieving and inhibiting chemotherapy-related gastrointestinal toxicity.

[0029] Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0030] The present invention proposes to use polyprezinc as an active ingredient to alleviate gastrointestinal toxicity caused by chemotherapy, expands its new use in the field of medicine, and provides a new choice for the development of drugs for alleviating and inhibiting chemotherapy-related gastrointestinal toxicity. Polyprezinc is used to alleviate the gastrointestinal toxicity caused by irinotecan, and a gastrointestinal toxicity model is constructed using BALB / c mice. The alleviating effect of polyprezinc on the gastrointestinal toxicity caused by irinotecan is detected by measuring the changes in mouse body weight and intestinal length, and the pathological changes in the ileum and colon tissues of the mice. The results show that polyprezinc can alleviate the gastrointestinal toxicity caused by irinotecan. It shortens the intestinal length of mice, improves irinotecan-induced ileal damage in mice and reduces inflammation, significantly improves the intestinal barrier function of mice, and can effectively reduce the gastrointestinal toxicity caused by irinotecan. In addition, polypregnenol zinc has excellent stability and solubility, can avoid additional residues while meeting the normal needs of the body, and has low toxicity to the body. Therefore, when used to prevent and treat chemotherapy-induced gastrointestinal toxicity, drugs containing polypregnenol zinc have the advantages of a safe dosage range, significant and rapid efficacy, low cost, and no drug resistance and drug residue, and have broad application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The figure shows the technical route of mouse modeling, the changes in mouse weight and the changes in ileum length. Figure 1 A is the technical roadmap for the irinotecan-induced mouse diarrhea model and drug intervention; Figure 1 B is the result of the change of small intestine length in model mice; Figure 1 C is a graph showing the changes in colon length in model mice. Figure 1 D is a curve chart showing the percentage change in body weight of model mice.

[0032] Figure 2 This is a comparison of HE staining of ileum and colon pathological sections of two groups of mice. Figure 2 A is the HE staining result of mouse ileum pathological section; Figure 2 B is the result of ileum pathology scoring; Figure 2 C. HE staining results of mouse colon pathological sections; Figure 2 D is the colon pathology scoring result (scale bar is 100 μm). DETAILED DESCRIPTION

[0033] The content of the present invention is specifically described below by examples. In the present invention, the following examples are for better explanation of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications may be made to the present invention without departing from the spirit and scope of the present invention.

[0034] Experimental reagents: Polaprezinc was purchased from Shanghai MacLean Biochemical Technology Co., Ltd. (Batch No.: #C16839653), irinotecan was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (Batch No.: #G2410410), L-lactic acid (C3H6O3) was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd. (Batch No.: #G2017197), and sorbitol (C6 H14O6) was purchased from Shanghai San Chemical Technology Co., Ltd. (Batch No.: DC120008).

[0035] Experimental instruments: electronic balance, panoramic tissue scanner (NanoZoomer S60), upright fluorescence microscope (BX53).

[0036] Example 1

[0037] This example provides the use of polyprezinc in alleviating the effects of irinotecan on mouse body weight and intestinal length:

[0038] (1) Irinotecan injection: preheat 20%-30% of the total amount of water for injection (normal saline) and 34 μl of lactic acid at 85°C, add 277 mg of irinotecan powder, quickly add water for injection to 95% of the total amount, stir thoroughly, add 225 mg of D-sorbitol until completely dissolved, add water for injection to a sufficient amount of 40 ml, filter using a 0.22 μm filter membrane, and store at 4°C away from light for later use. At the same time, the polyprene zinc solution is prepared by dissolving it in ultrapure water and using ultrasound to assist dissolution.

[0039] (2) Experimental animals and model preparation: Healthy SPF-grade female BALB / c mice (purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were selected. They were 6 weeks old and weighed 16-18 g and were adaptively fed at 25±2°C for one week.

[0040] (3) Grouping and treatment: After the adaptive feeding, the mice were randomly divided into a control group and a polyprezinc group (n = 6 mice in each group). The two groups of mice received intraperitoneal injection of irinotecan injection (the dosage for mice was 25 mg / kg) once a day. The mice in the control group were given normal drinking water, and the mice in the polyprezinc group were given drinking water containing 100 mg / kg polyprezinc according to their body weight. The drinking water was changed once a day. The weight changes, diarrhea and mortality of the mice in each group were observed. The mice were killed on the 8th day to examine the physiological and biochemical indicators and intestinal damage of the mice, such as Figure 1 As shown in A.

[0041] (4) Data processing: All data were expressed as Mean ± SEM and processed using GraphPad Prism software. The two-sided unpaired t-test was used to test for statistical significance. P < 0.05 was considered a significant difference.

[0042] (5) Assessment of mouse body weight: The body weight of mice in the control group and the polyprezinc group was measured every day. Figure 1 As shown in B, polyprednisolone zinc could not improve the weight loss of mice induced by irinotecan.

[0043] (6) Evaluation of intestinal length: After one week of feeding (the feeding age is calculated from the start of feeding with polyprene zinc drinking water), the length of the small intestine and colon of the mice was measured. The results are as follows: Figure 1 As shown in C and 1D, compared with the model group, the intestinal length of the experimental mice increased significantly after taking polyprednisolone, indicating that polyprednisolone can alleviate the shortening of the intestinal length of mice caused by irinotecan.

[0044] Example 2

[0045] This example provides the effect of polyprezinc on irinotecan-induced pathological changes in the ileum and colon of mice:

[0046] (1) Pathological examination: The mouse ileum and colon tissue samples from Example 1 were fixed in 4% paraformaldehyde solution for histopathological examination. The mouse ileum and colon tissues were embedded in paraffin, sliced, and stained with HE (hematoxylin-eosin) and then placed under an upright fluorescence microscope (BX53) to observe the pathological morphological changes of the tissues. A panoramic tissue scan was performed using a digital slice scanner NanoZoomer S60. The scanning results are shown in the figure. Figure 2 As shown, compared with the control group, the ileum and colon villi structure of mice in the polyprednisolone group was more intact, and the degree of inflammation was lower, indicating that polyprednisolone can significantly improve the intestinal damage caused by irinotecan in mice, protect the intestinal barrier function of mice, and significantly reduce the gastrointestinal toxicity caused by irinotecan.

[0047] (2) Data processing: All data were expressed as Mean ± SEM and processed using GraphPad Prism software. The two-sided unpaired t-test was used to test for statistical significance. P < 0.05 was considered a significant difference.

[0048] (3) HE pathological scoring criteria: The histological criteria of Neurath et al. were used for scoring, with the severity of the lesions scored as 1 (mild; no destruction of the villus structure, low-level inflammatory infiltration), 2 (mild; deepening of intestinal crypts, thickening of the intestinal wall, moderate-level inflammatory infiltration, no ulcers), 3 (moderate; vascular hyperplasia, thickening of the intestinal wall, high-level inflammatory infiltration, no ulcers) and 4 (severe: vascular hyperplasia, deepening and deformation of intestinal crypts, thickening of the intestinal wall and invasion of the muscular layer, obvious inflammatory infiltration, accompanied by ulcers). No obvious lesions were scored as 0 points.

[0049] (4) Test results: Figure 2 A and Figure 2 B shows that compared with the model group, the ileal villus length and crypt height of the mice in the polyprednisolone group were significantly restored, and the pathological score was significantly decreased, indicating that polyprednisolone has a protective effect on the intestinal damage of mice caused by irinotecan; Figure 2 C and Figure 2 As shown in D, compared with the model group, the colon villus structure of the mice in the polyprednisolone group was more intact, the degree of inflammation was lower, and the pathological score was significantly decreased. Polyprednisolone can significantly improve the intestinal barrier damage of mice caused by irinotecan and effectively alleviate the intestinal toxicity caused by it.

[0050] In summary, polyprezinc can alleviate the intestinal mucosal damage caused by the chemotherapy drug irinotecan in mice, improve the intestinal barrier, and effectively reduce the intestinal toxicity caused by irinotecan. Therefore, combined with polyprezinc intervention during chemotherapy in clinical colorectal cancer patients, it is expected to resolve the delayed diarrhea caused by irinotecan, and provide potential application value for improving the quality of life of clinical irinotecan chemotherapy patients and the smooth implementation of chemotherapy.

Claims

1. Application of polyprezinc in the preparation of drugs for alleviating gastrointestinal toxicity caused by chemotherapy.

2. Use of polyprene zinc or a pharmaceutically acceptable salt thereof in the preparation of a drug for alleviating gastrointestinal toxicity caused by chemotherapy.

3. Use of polyprene zinc or a pharmaceutically acceptable salt thereof in the preparation of a drug for alleviating gastrointestinal toxicity caused by irinotecan.

4. The use according to claim 1, characterized in that: The polyprene zinc is a chelate of zinc and L-carnosine.

5. The use according to claim 1, characterized in that: The polyprenatine zinc is preferably administered to mammals at a dose of 50-150 mg / kg body weight for use in alleviating gastrointestinal toxicity caused by chemotherapy.

6. The use according to claim 1, characterized in that: The polyprene zinc can alleviate intestinal villus damage and thus reduce the gastrointestinal toxicity caused by the chemotherapy drug irinotecan.

7. A pharmaceutical composition for alleviating gastrointestinal toxicity caused by chemotherapy, characterized in that: The pharmaceutical composition contains polyprene zinc as an active ingredient and a pharmaceutically acceptable carrier or excipient.

8. The pharmaceutical composition according to claim 7, characterized in that The dosage form of the pharmaceutical composition is granules, tablets, capsules, oral liquids, pills, emulsions or suspensions, injections, infusions or sprays.

9. Use of a pharmaceutical composition for alleviating gastrointestinal toxicity caused by chemotherapy in the preparation of a drug for alleviating gastrointestinal toxicity caused by chemotherapy.

10. The pharmaceutical composition according to claim 9, characterized in that The pharmaceutical composition is used in preparing a drug for alleviating gastrointestinal toxicity caused by irinotecan.

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