Zinc polyphenol complex suppository as well as preparation method and application thereof

Abstract

The invention discloses a zinc polyphenol complex suppository as well as a preparation method and application thereof. The preparation process mainly comprises two steps as follows: a, preparation of EGCG-Zn metal polyphenol complex nanoparticles; and b, preparing the nano complex suppository. The method is simple in process, green, environment-friendly and suitable for large-scale preparation. The prepared EGCG-Zn nanoparticles are uniform in particle size and good in stability, and have good antioxidant, anti-inflammatory and tissue repair activity based on a complex network structure formed by self-assembly of EGCG and zinc ions. The nano-particles are firstly treated by adopting a drug pretreatment carrier and then loaded in a suppository matrix to construct a rectal administration type nano-suppository, so that targeted and continuous local drug effect release can be realized. In intervention of radioactive intestinal injury, the suppository not only can relieve oxidative stress and inflammatory response, but also can promote regeneration and repair of intestinal mucosa, and has good treatment potential and clinical application prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine and pharmaceutical preparations, and particularly relates to a zinc polyphenol complex suppository and a preparation method and application thereof. Background Art

[0002] Radiation-induced intestinal injury (RIII) is a common and serious complication of tumor radiotherapy that affects treatment compliance. The incidence and harm of radiation-induced intestinal injury are more prominent in the treatment of pelvic tumors such as rectal cancer, prostate cancer and cervical cancer. Its pathogenesis mainly includes oxidative stress, release of inflammatory factors, intestinal barrier destruction and cell apoptosis, which can lead to serious life-threatening consequences such as diarrhea, abdominal pain, intestinal bleeding, infection and even intestinal perforation. At present, the clinical treatment of radiation-induced intestinal injury is still mainly symptomatic supportive treatment, such as antidiarrheal drugs, glucocorticoids, antibiotics and nutritional support. There is still a lack of effective preventive or therapeutic drugs with targeted and specificity. Studies have shown that oxidative stress and inflammatory response play a key role in the early stage of RIII. Targeted intervention in these two links may effectively delay the occurrence and development of intestinal injury.

[0003] Natural polyphenols, particularly epigallocatechin gallate (EGCG), have been extensively studied for their potential to mitigate radiotherapy-induced tissue damage due to their rich phenolic hydroxyl groups and their excellent free radical scavenging, antioxidant, and anti-inflammatory activities. However, EGCG itself suffers from poor stability, susceptibility to oxidation, rapid metabolism, and low bioavailability, limiting its application in treating intestinal damage. Zinc (Zn), an essential trace element, has been shown to not only possess antioxidant and anti-inflammatory properties but also promote intestinal mucosal regeneration and repair, a key mechanism of intestinal protection. EGCG complexes with zinc ions to form metallo-polyphenol complexes, which not only significantly enhance EGCG's stability but also potentially exert protective effects through distinct mechanisms involving EGCG and Zn. Furthermore, traditional oral drug delivery methods are subject to the influence of the digestive tract environment, making it difficult to effectively control the location of drug release, potentially leading to localized drug absorption and inadequate efficacy. Therefore, rectal delivery of EGCG-Zn nanocomplexes via suppository form can achieve in situ sustained release of the drug at the site of rectal injury, enhancing local absorption and duration of action, and providing more site-specific protection against rectal injury. Furthermore, due to absorption in the rectal venous plexus, the drug can be absorbed there and circulate throughout the body, potentially providing a backup solution for radiation-induced damage elsewhere. The challenge of forming structurally uniform, size-controlled nanoparticles and simultaneously forming a stable, controlled-release suppository to achieve effective synergistic preventive and therapeutic effects is currently under investigation.

[0004] In summary, the present invention provides an EGCG-Zn metal polyphenol complex nanoparticle suppository, in which EGCG-Zn nanoparticles are obtained through PVP-NMP system-assisted complexation, ethanol-induced precipitation and freeze-drying process, and then compounded with a suppository matrix to form a highly uniform suppository, achieving targeted delivery, stable controlled release and synergistic therapeutic effects of multiple mechanisms, providing a new solution for the prevention and treatment of radiation injury. Summary of the Invention

[0005] The present invention aims to address the deficiencies in existing methods for preventing and treating radiation damage and to provide a zinc polyphenol (EGCG-Zn) complex suppository, a preparation method, and applications thereof. The method enables EGCG to react with Zn to generate stable, highly dispersible, and uniform metal polyphenol complex nanoparticles with controllable particle size. The method also avoids the production of hydrolysis byproducts and enables the formation of a highly uniform suppository with a matrix. The preparation method is simple and stable. The suppository can be used for local protective treatment of radiation damage, such as radiation-induced intestinal damage, and for promoting mucosal repair.

[0006] In order to achieve the above-mentioned purpose, the present invention adopts the following technical measures: A method for preparing a zinc polyphenol complex suppository comprises the following steps: 1) EGCG-Zn complex nanoparticles with uniform particle size were prepared based on PVP-NMP system-assisted complexation, ethanol-induced precipitation, and freeze-drying process; 2) The EGCG-Zn complex nanoparticles obtained in 1) are pretreated based on a drug pretreatment carrier, and then compounded with a suppository matrix to prepare the zinc polyphenol complex suppository.

[0007] In the above technical solution, further, step 1) is specifically as follows: The polyvinyl pyrrolidone (PVP) powder is dissolved in N-methyl pyrrolidone (NMP) by ultrasonication to completely dissolve the solution to form a PVP-NMP solution, zinc salt is added thereto to obtain a zinc ion solution, and the solution is stirred after ultrasonication. Epigallocatechin gallate EGCG was dissolved in NMP and completely dissolved by ultrasonication to form EGCG-NMP solution; Under stirring conditions, the EGCG-NMP solution was added dropwise to the zinc ion solution, and the reaction was stirred in the dark. After the reaction was completed, anhydrous ethanol was added to induce precipitation, and the mixture was washed with water after centrifugation and vacuum freeze-dried to obtain EGCG-Zn complex nanoparticles.

[0008] Furthermore, the zinc salt is one or more of zinc acetate, zinc nitrate or zinc sulfate.

[0009] Furthermore, the PVP concentration in the PVP-NMP solution is 0.01-150 mM, the zinc concentration in the zinc ion solution is 0.02-200 mM, the EGCG concentration in the EGCG-NMP solution is 0.01-100 mM, and the EGCG-NMP solution and the zinc ion solution are equal in volume.

[0010] Furthermore, the volume of the anhydrous ethanol is 1-30 times the volume of the reaction solution.

[0011] Furthermore, step 2) is specifically as follows: The EGCG-Zn complex nanoparticles obtained in 1) were mixed with the drug pre-treated carrier pre-cooled to 0-5°C, and ground in an ice bath to form a paste, which was then sealed for later use; The PEG polymer and the drug release modifier are used as main components, melt-mixed at 60-65°C, and stirred continuously until completely homogeneous to obtain a suppository base; The suppository base is cooled to 52-58° C., the paste is added, and the mixture is stirred and dispersed to obtain a melt. The suppository mold is then preheated at 50-55° C. After preheating, a release agent is applied to the inner side of the mold for lubrication. The melt is rapidly injected into the preheated mold to avoid bubbles. The melt overflows a layer on the surface and is then gradient cooled and solidified. After it is completely solidified, the overflowed portion is cut off and the mold is removed to obtain the zinc polyphenol complex suppository.

[0012] Furthermore, the suppository matrix is ​​composed of 6-10 parts of PEG polymer, 1-2 parts of drug release modifier and 0-1.5 parts of water, in parts by mass, wherein the PEG polymer is a mixture of 2-3 of PEG-1500, PEG-4000 and PEG-6000, and the drug release modifier is a nonionic surfactant.

[0013] Furthermore, the mass ratio of the nanoparticles to the drug pretreatment carrier is 0.1-100, more preferably 0.2-4, and the drug pretreatment carrier is at least one of glycerol, propylene glycol, and polyethylene glycol 400.

[0014] A zinc polyphenol complex suppository is prepared by any of the above preparation methods.

[0015] Use of the zinc polyphenol complex suppository as described above in preparing medicine for treating radiation damage.

[0016] Compared with the prior art, the present invention has the following advantages and effects: The present invention provides a locally delivered antioxidant nanosuppository based on the synergistic construction of EGCG-Zn metal polyphenol complex nanoparticles and a drug carrier. The preparation process is simple and stable, making it suitable for large-scale production and promising for clinical application. By incorporating a self-assembly complexation mechanism between epigallocatechin gallate (EGCG) and zinc ions, metal polyphenol complex nanoparticles with controllable particle size, stable structure, and excellent dispersibility were successfully prepared in an anhydrous environment. Furthermore, the complex nanoparticles were thoroughly mixed with a drug-pretreated carrier and then loaded into a multi-component hydrophilic matrix to construct a suppository system. This method effectively avoids the effects of hydrolysis byproducts on the purity of the complex, oxidation of EGCG, and the effects of suppository preparation temperature on the complex, thereby effectively ensuring the stability of the complex. The resulting suppository exhibits excellent physical and mechanical properties at room temperature, with an appropriate hardness (approximately 30-80 N) and formability, making it convenient for anorectal administration. It rapidly softens and disintegrates at body temperature, achieving a combination of rapid onset and sustained release. Over 90% of the drug is released within 1–2 hours, meeting the concentration maintenance and sustained efficacy required for local treatment. This formulation also exhibits excellent physicochemical stability and mucosal biocompatibility, significantly enhancing the synergistic antioxidant and anti-inflammatory effects of EGCG and zinc ions, and effectively promoting intestinal mucosal repair and barrier function reconstruction. It is suitable for the treatment of radiation-induced damage, particularly in the prevention and adjuvant treatment of intestinal damage caused by tumor radiotherapy or concurrent chemoradiotherapy, demonstrating excellent safety and application potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 This is a scanning electron microscope (SEM) photograph of the EGCG-Zn metal polyphenol complex nanoparticles synthesized in Example 1.

[0018] Figure 2 High-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) images of the EGCG-Zn metal polyphenol complex nanoparticles synthesized in Example 2 and the corresponding C (carbon), O (oxygen), and Zn (zinc) element mapping (EDS) images.

[0019] Figure 3 This is the absorption spectrum of the EGCG-Zn metal polyphenol complex nanoparticles and EGCG synthesized in Example 3.

[0020] Figure 4 This is the dynamic light scattering (DLS) hydrated particle size distribution diagram of the EGCG-Zn metal polyphenol complex nanoparticles synthesized in Example 1 and prepared in an aqueous environment.

[0021] Figure 5 This is a trend diagram of the drug release rate of the EGCG-Zn complex suppository synthesized in Example 1 in simulated intestinal fluid over time.

[0022] Figure 6 This is a Ki67 immunohistochemical staining image of the rectum of mice using the EGCG-Zn complex suppository synthesized in Example 2 for protective treatment of radiation-induced rectal injury. DETAILED DESCRIPTION

[0023] The following describes the specific implementation of the embodiment of the present invention in detail with reference to the accompanying drawings. It should be understood that the specific implementation described herein is only used to illustrate and explain the embodiment of the present invention and is not used to limit the embodiment of the present invention.

[0024] It should be noted that, in the absence of conflict, the embodiments of the present invention and the features in the embodiments may be combined with each other.

[0025] According to some embodiments of the present invention, the method for preparing the zinc-polyphenol complex suppository of the present invention comprises the following steps: a. Preparation of EGCG-Zn complex nanoparticles A certain amount of polyvinylpyrrolidone (PVP) powder was weighed and dissolved in a single-necked flat-bottom flask containing N-methylpyrrolidone (NMP) to prepare a 0.01-150 mM PVP-NMP solution. The solution was then placed in an ultrasonic cleaner for 1-30 minutes to completely dissolve. A certain amount of zinc salt was then weighed and dissolved in the PVP-NMP solution to form a zinc ion solution with a molar concentration of 0.02-200 mM. The flask was ultrasonically dissolved again and stirred at 800-1200 rpm for at least 30 minutes. This stirring allowed the zinc ions to bind to the PVP through weak interactions such as coordination bonding, electrostatic interactions, hydrogen bonding, and spatial encapsulation, forming a pre-template for subsequent chelation with EGCG, which helped improve the stability and dispersibility of the material. Take another single-necked flat-bottom flask and add the same volume of NMP. Weigh a certain amount of epigallocatechin gallate EGCG and dissolve it in NMP to prepare a 0.01-100mM EGCG-NMP solution. The volume of the solution is consistent with the zinc ion solution. After ultrasonic dissolution for 1-30 minutes, after it is completely dissolved, it is slowly added dropwise to the stirring zinc ion solution. Stirring is continued for 1-36 hours under light-proof conditions. After the reaction is completed, add 1-30 times the volume of anhydrous ethanol to induce precipitation. After centrifugation, wash with water for more than three times, and vacuum freeze-dry to obtain EGCG-Zn complex nanoparticles. b. Preparation of EGCG-Zn Complex Suppositories The EGCG-Zn complex nanoparticles obtained in step a are mixed with a drug pretreatment carrier precooled to 0-5°C at a mass ratio of 0.1-100 (more preferably 0.2-4), and ground in an ice bath to form a paste, so that the drug pretreatment carrier forms a protective film on the surface of the nanoparticles, and then sealed for later use. The weight proportions of different components of the suppository matrix are 6-10 parts of 2-3 different PEG polymers, 1-2 parts of a drug release modifier, and 0-1.5 parts of water. The components are melted and mixed at 60-65° C. and stirred continuously for 10-30 minutes until completely homogenized. The temperature is then maintained at about 60° C. The matrix is ​​cooled to 52-58° C., and the EGCG-Zn complex nanoparticle paste is added. The matrix is ​​stirred and dispersed. The suppository mold is then preheated in a 50-55° C. oven. After preheating, the mold is lubricated with a release agent. The melt is quickly injected into the preheated mold to avoid bubbles. The matrix overflows a layer on the surface and is gradient cooled and solidified. After it is completely solidified, the overflowing part is cut off and demolded to obtain the EGCG-Zn complex suppository.

[0026] In some embodiments of the present invention, the zinc salt is preferably selected from zinc nitrate, zinc acetate or zinc sulfate.

[0027] In some embodiments of the present invention, the drug pretreatment carrier is preferably at least one of glycerol, propylene glycol, and polyethylene glycol 400.

[0028] In some embodiments of the present invention, the PEG polymer in the suppository base is preferably a mixture of 2-3 of PEG-1500, PEG-4000, and PEG-6000 to meet the melting temperature and injection molding requirements.

[0029] In some embodiments of the present invention, the drug release regulator is preferably a non-ionic surfactant, including but not limited to polyoxyethylene stearate, Tween 80, Span 40, etc.

[0030] In some embodiments of the present invention, the release agent is preferably selected from liquid paraffin, glycerol, vegetable oil (such as olive oil), polyethylene glycol 400, and other substances with good biocompatibility and demolding properties. It is used to coat the inner wall of the mold before the suppository is molded to assist in the smooth demolding of the EGCG-Zn complex suppository.

[0031] The above scheme can effectively avoid the use of water environment in the preparation of the complex, and there is no need to adjust the pH, which effectively avoids the problems of EGCG oxidation in water environment and Zn ion hydrolysis byproducts. In addition, in the present invention, after the EGCG-Zn complex nanoparticles are prepared, they are first pre-treated into a paste using a pre-cooled drug pretreatment carrier and sealed for standby use, and then mixed with a suppository base for suppository preparation. Compared with directly mixing the EGCG-Zn complex nanoparticles with the drug pretreatment carrier and the suppository base to prepare suppositories, it can effectively avoid the influence of high temperature on the complex during the suppository preparation process, protect the stability of the EGCG-Zn nanoparticle structure, prevent excessive oxidation of EGCG, protect the surface-modified PVP, maintain the dispersibility of the nanoparticles, avoid agglomeration, and prevent the oxidation of Zn ions that reduce their release capacity. The metal polyphenol complex EGCG-Zn nanoparticles prepared by the method of the present invention are regular spherical or nearly spherical small particle size particles with uniform particle size, a size range of 1-100nm, and excellent dispersibility. The resulting suppositories have a hardness range of 30–80 N and can be stored for long periods at room temperature. They soften and disintegrate rapidly at rectal body temperature (approximately 37°C), with initial drug release within 2–5 minutes, over 50% release within 30 minutes, and over 90% complete release within 60–120 minutes. These suppositories exhibit rapid onset and sustained local action. The synergistic effects of EGCG's antioxidant and anti-inflammatory properties and zinc ion's ability to promote epithelial repair, combined with their local rectal release properties, could be used to treat radiation-induced injury.

[0032] Example 1

[0033] A method for preparing zinc polyphenol EGCG-Zn complex suppositories, comprising the following steps: a. Preparation of EGCG-Zn Complex Nanoparticles: Weigh 30 mg of polyvinylpyrrolidone (PVP) and dissolve it in 5 ml of N-methylpyrrolidone (NMP) in a single-necked flat-bottom flask. Place in an ultrasonic bath for 5 minutes to completely dissolve. Separately, weigh 22.83 mg of zinc acetate dihydrate (Zn(CH3COO)2·2H2O) and dissolve it in 5 ml of the PVP-NMP solution. Place in an ultrasonic bath for approximately 5 minutes to completely dissolve the solution, resulting in a clear, transparent solution. Add a magnetic stir bar to the zinc acetate-PVP-NMP solution and stir at 1200 rpm for approximately 30 minutes. In a separate single-necked flat-bottom flask, weigh 23.8 mg of epigallocatechin gallate (EGCG) and dissolve it in 5 mL of N-methylpyrrolidone (NMP). The volume of the solution should be the same as that of the zinc ion solution. After ultrasonic dissolution for 5 minutes, use a pipette to slowly add the EGCG to the stirring zinc acetate-PVP-NMP solution after complete dissolution. Stir for 24 hours in the dark. After the reaction is complete, add 20 mL of anhydrous ethanol to induce precipitation. After centrifugation, wash three times with water, and freeze-dry under vacuum to obtain EGCG-Zn complex nanoparticles. b. Preparation of EGCG-Zn complex suppositories: The EGCG-Zn complex nanoparticles obtained in step a were mixed with propylene glycol pre-cooled to 4°C at a mass ratio of 1:3, and ground in an ice bath to form a paste, which was then sealed and set aside. The suppository matrix is ​​composed of 4 parts of polyethylene glycol 6000 (PEG6000), 3 parts of polyethylene glycol 4000 (PEG4000), 2 parts of Tween 80, and 1 part of water in proportion by weight of different components. The components are melted and mixed at 65°C and stirred for 15 minutes until completely homogeneous. The temperature is then maintained at about 60°C, and the matrix is ​​cooled to 56°C. The EGCG-Zn complex nanoparticle paste is added and stirred to disperse. The suppository mold is then preheated in a 55°C oven. After preheating, the inner side of the mold is lubricated with vegetable oil. The melt is quickly injected into the preheated mold to avoid bubbles. The matrix overflows the surface and is then gradient cooled and solidified. After it is completely solidified, the overflowing part is cut off and demolded to obtain the antioxidant, anti-inflammatory, and pro-repair EGCG-Zn complex suppository.

[0034] Example 2

[0035] A method for preparing zinc polyphenol EGCG-Zn complex suppositories, comprising the following steps: a. Preparation of EGCG-Zn Complex Nanoparticles: Weigh 40 mg of polyvinylpyrrolidone (PVP) and dissolve it in 10 ml of N-methylpyrrolidone (NMP) in a single-necked flat-bottom flask. Place in an ultrasonic bath for 5 minutes to completely dissolve. Separately, weigh 19.66 mg of zinc nitrate (Zn(NO₃)₂) and dissolve it in 10 ml of the PVP-NMP solution. Place in an ultrasonic bath for approximately 5 minutes to completely dissolve the solution, resulting in a clear, transparent solution. Add a magnetic stir bar to the zinc acetate-PVP-NMP solution and stir at 1200 rpm for approximately 30 minutes. In a separate single-necked flat-bottom flask, weigh 47.6 mg of epigallocatechin gallate (EGCG) and dissolve it in 10 mL of N-methylpyrrolidone (NMP). The volume of the solution should be the same as that of the zinc ion solution. After ultrasonic dissolution for 5 minutes, use a pipette to slowly add the EGCG to the stirring zinc acetate-PVP-NMP solution after complete dissolution. Stir for 24 hours in the dark. After the reaction is complete, add 60 mL of anhydrous ethanol to induce precipitation. After centrifugation, wash three times with water, and freeze-dry under vacuum to obtain EGCG-Zn complex nanoparticles. b. Preparation of EGCG-Zn complex suppositories: The EGCG-Zn complex nanoparticles obtained in step a were mixed with glycerol pre-cooled to 4°C at a mass ratio of 1:2, and ground in an ice bath to form a paste, which was then sealed and set aside. The suppository matrix is ​​composed of 5 parts of polyethylene glycol 4000 (PEG6000), 4 parts of polyethylene glycol 6000 (PEG4000), 2 parts of polyoxyethylene stearate, and 1 part of water in proportion to the weight of different components. The components are melted and mixed at 65°C, stirred for 15 minutes until completely homogeneous, and then the temperature is maintained at about 60°C. The matrix is ​​cooled to 56°C, and the EGCG-Zn complex nanoparticle paste is added and stirred to disperse. The suppository mold is then preheated in a 55°C oven. After preheating, the inner side of the mold is lubricated with liquid paraffin, and the melt is quickly injected into the preheated mold to avoid bubbles. The matrix overflows the surface and is gradient cooled and solidified. After it is completely solidified, the overflowing part is cut off and demolded to obtain the antioxidant, anti-inflammatory and pro-repair EGCG-Zn complex suppository.

[0036] Example 3

[0037] A method for preparing zinc polyphenol EGCG-Zn complex suppositories, comprising the following steps: a. Preparation of EGCG-Zn Complex Nanoparticles: Weigh 300 mg of polyvinylpyrrolidone (PVP) and dissolve it in 50 ml of N-methylpyrrolidone (NMP) in a single-necked flat-bottom flask. Place in an ultrasonic bath for 5 minutes to completely dissolve. Separately, weigh 228.3 mg of zinc acetate dihydrate (Zn(CH3COO)2·2H2O) and dissolve it in 50 ml of the PVP-NMP solution. Place in an ultrasonic bath for approximately 5 minutes to completely dissolve the solution, resulting in a clear, transparent solution. Add a magnetic stir bar to the zinc acetate-PVP-NMP solution and stir at 1200 rpm for approximately 30 minutes. In a separate single-necked flat-bottom flask, weigh 238 mg of epigallocatechin gallate (EGCG) and dissolve it in 50 mL of N-methylpyrrolidone (NMP). The volume of the solution should be the same as that of the zinc ion solution. After ultrasonic dissolution for 5 minutes, use a pipette to slowly add the EGCG to the stirring zinc acetate-PVP-NMP solution after complete dissolution. Stir for 24 hours in the dark. After the reaction is complete, add 200 mL of anhydrous ethanol to induce precipitation. After centrifugation, wash three times with water, and freeze-dry under vacuum to obtain EGCG-Zn complex nanoparticles. b. Preparation of EGCG-Zn complex suppositories: The EGCG-Zn complex nanoparticles obtained in step a were mixed with glycerol pre-cooled to 4°C at a mass ratio of 1:2, and ground in an ice bath to form a paste, which was then sealed and set aside. The suppository matrix is ​​composed of 5 parts of polyethylene glycol 4000 (PEG6000), 4 parts of polyethylene glycol 6000 (PEG4000), 2 parts of polyoxyethylene stearate, and 1 part of water in proportion to the weight of different components. The components are melted and mixed at 65°C, stirred for 15 minutes until completely homogeneous, and then the temperature is maintained at about 60°C. The matrix is ​​cooled to 56°C, and the EGCG-Zn complex nanoparticle paste is added and stirred to disperse. The suppository mold is then preheated in a 55°C oven. After preheating, the inner side of the mold is lubricated with liquid paraffin, and the melt is quickly injected into the preheated mold to avoid bubbles. The matrix overflows the surface and is gradient cooled and solidified. After it is completely solidified, the overflowing part is cut off and demolded to obtain the antioxidant, anti-inflammatory and pro-repair EGCG-Zn complex suppository.

[0038] The scanning electron microscope (SEM) images of the EGCG-Zn metal polyphenol complex nanoparticles synthesized in Example 1 are as follows: Figure 1 As shown, it can be clearly seen that the EGCG-Zn complex presents an aggregated nanoparticle structure, with a particle size mainly distributed in the range of tens to hundreds of nanometers, a rough particle surface, and a uniform morphology. The high-angle annular dark field scanning transmission electron microscopy (HAADF-STEM) image of the EGCG-Zn metal polyphenol complex nanoparticles synthesized in Example 2 and the corresponding C (carbon), O (oxygen), and Zn (zinc) element mapping (EDS) are shown in FIG. Figure 2 As shown in the figure, HAADF-STEM and EDS images further illustrate the nanostructure and elemental composition of the EGCG-Zn nanocomplex. The HAADF photo shows that the particles have obvious pore structure, and the EDS photo shows that C, O and Zn elements are evenly distributed in the particles, indicating that zinc ions and EGCG are evenly embedded in the system through self-assembly complexation to form a stable metal polyphenol complex network. Figure 3 This is the absorption spectrum of the EGCG-Zn metal polyphenol complex nanoparticles and EGCG synthesized in Example 3. It can be seen that EGCG presents a broad peak of hydroxyl characteristic stretching vibration near 3400 cm⁻¹, and a characteristic peak of benzene ring skeleton vibration in the 1600-1400 cm⁻¹ region. The peak shape and peak position of the EGCG-Zn complex in the EGCG hydroxyl and benzene ring related characteristic peaks change significantly, indicating that the active groups in the EGCG molecule coordinate with Zn²⁺, and the EGCG-Zn complex structure is successfully constructed.

[0039] The PVP-NMP system in Example 1 was replaced with a PVP-water environment system (NMP was replaced with deionized water) to obtain zinc polyphenol complex nanoparticles. The dynamic light scattering (DLS) hydrated particle size distribution of the two is shown in FIG. Figure 4 As shown, it can be seen that the particle size distribution of the complex nanoparticles prepared by the method of the present invention shows a clear single peak feature, without interference from secondary peaks, and the main particle size is concentrated around 150 nm (the presence of PVP on the surface makes the DLS size larger than the dry size under TEM), the particle size distribution width is narrow, and the dispersion is uniform, indicating that the EGCG-Zn complex nanoparticles prepared by the PVP-NMP system have better monodispersity and better particle size uniformity, which is more conducive to uniform dispersion on the intestinal surface in subsequent suppository applications.

[0040] Figure 5 This is a graph showing the time-dependent release rate of the EGCG-Zn complex suppository synthesized in simulated intestinal fluid from Example 1. It can be seen that the EGCG dissolution and release rate of the synthesized complex suppository in simulated intestinal fluid is initially gentle, then increases significantly around 20-40 minutes, and the drug is completely released in the later stages. Figure 6The EGCG-Zn complex suppositories synthesized in Example 2 were used for the protective treatment of radiation-induced rectal injury in mice. Radiation-induced rectal injury was induced by local X-ray irradiation of the mouse rectum, followed by local treatment with EGCG-Zn complex suppositories. Ten days after treatment, the mice were euthanized. Rectal Ki67 immunohistochemical staining images were obtained for healthy control mice, irradiation groups, and irradiation + drug administration groups. Comparative analysis of the immunohistochemical staining results for rectal Ki67 in mice from different treatment groups revealed that the EGCG-Zn complex suppositories effectively reversed radiation-induced intestinal damage by increasing the proportion of Ki67-positive cells in intestinal tissue and activating the epithelial cell proliferation and repair mechanism.

[0041] The foregoing is merely an embodiment of the present invention and is not intended to limit the present invention. It will be apparent to those skilled in the art that various modifications and variations of the present invention are possible. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention are intended to be included within the scope of the claims of the present invention.

Claims

1. A method for preparing zinc polyphenol complex suppositories, characterized in that: These include: 1) EGCG-Zn complex nanoparticles with uniform particle size were prepared based on PVP-NMP system-assisted complexation, ethanol-induced precipitation, and freeze-drying process; 2) The EGCG-Zn complex nanoparticles obtained in 1) are pretreated based on a drug pretreatment carrier, and then compounded with a suppository matrix to prepare the zinc polyphenol complex suppository.

2. The method for preparing the zinc polyphenol complex suppository according to claim 1, wherein: Step 1) is as follows: The polyvinyl pyrrolidone (PVP) powder is dissolved in N-methyl pyrrolidone (NMP) by ultrasonication to completely dissolve the solution to form a PVP-NMP solution, zinc salt is added thereto to obtain a zinc ion solution, and the solution is stirred after ultrasonication. Epigallocatechin gallate EGCG was dissolved in NMP and completely dissolved by ultrasonication to form EGCG-NMP solution; Under stirring conditions, the EGCG-NMP solution was added dropwise to the zinc ion solution, and the reaction was stirred in the dark. After the reaction was completed, anhydrous ethanol was added to induce precipitation, and the mixture was washed with water after centrifugation and vacuum freeze-dried to obtain EGCG-Zn complex nanoparticles.

3. The method for preparing the zinc polyphenol complex suppository according to claim 2, wherein: The zinc salt is one or more of zinc acetate, zinc nitrate or zinc sulfate.

4. The method for preparing the zinc polyphenol complex suppository according to claim 2, wherein: The PVP concentration in the PVP-NMP solution is 0.01-150 mM, the zinc concentration in the zinc ion solution is 0.02-200 mM, the EGCG concentration in the EGCG-NMP solution is 0.01-100 mM, and the EGCG-NMP solution and the zinc ion solution are equal in volume.

5. The method for preparing the zinc polyphenol complex suppository according to claim 2, wherein: The volume of the anhydrous ethanol is 1-30 times the volume of the reaction solution.

6. The method for preparing the zinc polyphenol complex suppository according to claim 1, characterized in that: Step 2) is as follows: The EGCG-Zn complex nanoparticles obtained in 1) were mixed with the drug pre-treated carrier pre-cooled to 0-5°C, and ground in an ice bath to form a paste, which was then sealed for later use; The PEG polymer and the drug release modifier are used as main components, melt-mixed at 60-65°C, and stirred continuously until completely homogeneous to obtain a suppository base; The suppository base is cooled to 52-58° C., the paste is added, and the mixture is stirred and dispersed to obtain a melt. The suppository mold is then preheated at 50-55° C. After preheating, a release agent is applied to the inner side of the mold for lubrication. The melt is rapidly injected into the preheated mold to avoid bubbles. The melt overflows a layer on the surface and is then gradient cooled and solidified. After it is completely solidified, the overflowed portion is cut off and the mold is removed to obtain the zinc polyphenol complex suppository.

7. The method for preparing the zinc polyphenol complex suppository according to claim 6, characterized in that: The suppository matrix is ​​composed of 6-10 parts by mass of a PEG polymer, 1-2 parts of a drug release modifier, and 0-1.5 parts of water. The PEG polymer is a mixture of two or three of PEG-1500, PEG-4000, and PEG-6000. The drug release modifier is a nonionic surfactant.

8. The method for preparing the zinc polyphenol complex suppository according to claim 6, characterized in that: The mass ratio of the nanoparticles to the drug pretreatment carrier is 0.1-100, preferably 0.2-4, and the drug pretreatment carrier is at least one of glycerol, propylene glycol, and polyethylene glycol 400.

9. A zinc polyphenol complex suppository, characterized in that: The method is as described in any one of claims 1 to 8.

10. Use of the zinc-polyphenol complex suppository according to claim 9 in preparing a drug for treating radiation damage.

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