Curcumin suppository as well as preparation method and application thereof

Abstract

The invention discloses a curcumin suppository as well as a preparation method and application thereof, belongs to the technical field of drug-loaded nano-micelles, and particularly relates to a preparation method of the curcumin suppository. The preparation method specifically comprises the following steps: heating curcumin and polyethylene glycol at a high temperature, carrying out vortex oscillation until a clear solution is formed, adding Tween, uniformly mixing to obtain a dark brown clear liquid, pouring the dark brown clear liquid into a suppository mold, cooling, and demolding to obtain the curcumin suppository. The curcumin suppository prepared by the invention has high drug loading rate and excellent cancer cell inhibition effect, and the bioavailability and efficacy of curcumin are greatly improved.

Description

Technical Field

[0001] This invention relates to the field of drug-loaded nanomicelles, specifically to a curcumin suppository, its preparation method, and its application. Background Technology

[0002] Curcumin, a promising therapeutic compound, suffers from limited oral bioavailability due to its extremely poor solubility and rapid metabolism. The oral bioavailability of curcumin is constrained by multiple factors: extremely low water solubility at physiological pH conditions; extensive metabolism in the intestine and liver; rapid clearance; and easy degradation or inactivation in alkaline environments. Furthermore, dissolved curcumin is sensitive to ultraviolet light and may undergo photochemical degradation during experimental procedures. Current curcumin research primarily focuses on medicinal chemistry and pharmaceutical strategies aimed at improving its water solubility, chemical stability, and bioavailability, while simultaneously achieving targeted delivery to cancerous tissues. These strategies include: loading curcumin into liposomes, phospholipid carriers, solid lipid microparticles, cyclodextrins, hydrogels, or nanoparticles; developing transdermal patches and microsphere systems; constructing nanoemulsions; and synthesizing curcumin structural analogs. Existing curcumin products are mainly in oral dosage forms, with no reports on rectal suppositories. To address the aforementioned issues, it is necessary to develop a rectal suppository (solid dosage form) containing curcumin nanogels to significantly improve the bioavailability and efficacy of curcumin. Summary of the Invention

[0003] The purpose of this invention is to provide a curcumin suppository, its preparation method, and its application. By optimizing the preparation process of the curcumin suppository, the solubility of curcumin is increased, the drug loading rate of the curcumin suppository is significantly improved, and the inhibitory effect of the curcumin suppository on cancer cells is enhanced, thereby significantly improving the bioavailability and efficacy of the curcumin suppository.

[0004] The technical solution adopted by the present invention to achieve the above objectives is as follows: A method for preparing curcumin suppositories includes: heating curcumin and polyethylene glycol at high temperature and vortexing until a clear solution is formed; adding Tween and mixing evenly to obtain a dark brown clear liquid; pouring the dark brown clear liquid into a suppository mold; and demolding after cooling to obtain the curcumin suppository; the high temperature is 80-100℃; the ratio of curcumin to Tween is 1 g: 1-20 mL; the volume ratio of Tween to polyethylene glycol is 1:4-10; the solubility of curcumin in the suppository is 10-200 mg / mL; and the curcumin suppository spontaneously forms curcumin nanoparticles upon contact with water, with an average particle size of 137.1-320.1 nm.

[0005] This invention discloses a curcumin suppository that utilizes a polyethylene glycol (PEG) / Tween system to increase the solubility of curcumin. The high molecular weight of PEG causes curcumin nanomicelles to solidify at room temperature to form a suppository, while melting at body temperature and spontaneously forming curcumin nanoparticles upon contact with water, thus greatly improving the solubility and bioavailability of curcumin.

[0006] Preferably, the preparation method of curcumin suppositories includes heating curcumin and polyethylene glycol at high temperature and vortexing until a clear solution is formed, adding Tween and mixing evenly, adding alkenyl monomer solution and stirring for 2-5 h, then adding functional agent under nitrogen atmosphere and stirring for 2-5 h, pouring the reaction solution into suppository mold, cooling and demolding to obtain curcumin suppositories.

[0007] More preferably, the alkenyl monomer solution is a mixture of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, and dimethyl sulfoxide. This invention introduces 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether into curcumin nanomicelles for free radical polymerization, which may enhance the encapsulation capacity of the curcumin nanomicelle core, optimize the stability of the curcumin nanomicelles, and significantly increase the drug loading of curcumin suppositories, thus enabling curcumin suppositories to exhibit a significant inhibitory effect on cancer cells.

[0008] More preferably, the ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine is 1 mL: 0.1-0.3 g.

[0009] More preferably, the ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is 1 mL: 0.02-0.1 g.

[0010] More preferably, the functional agents include a solution of methylenebisacrylamide, an aqueous solution of ammonium persulfate, and an aqueous solution of tetramethylethylenediamine.

[0011] More preferably, the methylenebisacrylamide solution is a mixture of methylenebisacrylamide and dimethyl sulfoxide.

[0012] More preferably, the volume ratio of the methylenebisacrylamide solution to the ammonium persulfate aqueous solution is 1:0.2-1, and the volume ratio of the methylenebisacrylamide solution to the tetramethylethylenediamine aqueous solution is 1:0.5-2.

[0013] Preferably, the preparation method of curcumin suppositories is as follows: Curcumin is mixed with polyethylene glycol (PEG 1500) and heated at 80-100℃. The mixture is vortexed every 2-10 minutes until a clear solution is formed. Tween 20 is added and mixed evenly to obtain a dark brown clear liquid. The dark brown clear liquid is poured into a suppository mold, cooled, and then demolded to obtain curcumin suppositories.

[0014] More preferably, the ratio of curcumin to Tween is 1 g: 1-20 mL.

[0015] More preferably, the volume ratio of Tween to polyethylene glycol is 1:4-10.

[0016] Preferably, the preparation method of curcumin suppositories is as follows: Curcumin was mixed with polyethylene glycol (PEG 1500) and heated at 80-100℃. The mixture was vortexed every 2-10 minutes until a clear solution was formed. Tween 20 was added and mixed evenly. Then, an alkenyl monomer solution was added and stirred for 2-5 hours. Functional agent was added under a nitrogen atmosphere and stirred for 2-5 hours. The reaction solution was poured into a suppository mold, cooled, and then demolded to obtain curcumin suppositories.

[0017] More preferably, the ratio of curcumin to Tween is 1 g: 1-20 mL.

[0018] More preferably, the volume ratio of Tween to polyethylene glycol is 1:4-10.

[0019] More preferably, the alkenyl monomer solution is a mixture of at least one of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, and N-vinylacetamide with dimethyl sulfoxide. This invention further introduces N-vinylacetamide into the preparation of curcumin suppositories, which may improve the dispersion stability of curcumin nanomicelles, efficiently encapsulate curcumin, thereby further increasing the drug loading rate of curcumin suppositories and optimizing their tumor-suppressing effect.

[0020] More preferably, the ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine is 1 mL: 0.1-0.3 g.

[0021] More preferably, the ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is 1 mL: 0.02-0.1 g.

[0022] More preferably, the ratio of dimethyl sulfoxide to N-vinylacetamide is 1 mL: 0.02-0.1 g.

[0023] More preferably, the volume ratio of polyethylene glycol to alkenyl monomer solution is 1:0.02-0.1.

[0024] More preferably, the functional agents include a solution of methylenebisacrylamide, an aqueous solution of ammonium persulfate, and an aqueous solution of tetramethylethylenediamine.

[0025] More preferably, the N-methylenebisacrylamide solution is a mixture of N-methylenebisacrylamide and dimethyl sulfoxide, wherein the ratio of N-methylenebisacrylamide to dimethyl sulfoxide is 1 g: 2-10 mL.

[0026] More preferably, the concentration of the ammonium persulfate aqueous solution is 0.1-0.5 g / mL.

[0027] More preferably, the concentration of the tetramethylethylenediamine aqueous solution is 0.1-0.5 g / mL.

[0028] More preferably, the volume ratio of the methylenebisacrylamide solution to the ammonium persulfate aqueous solution is 1:0.2-1.

[0029] More preferably, the volume ratio of the methylenebisacrylamide solution to the tetramethylethylenediamine aqueous solution is 1:0.5-2.

[0030] More preferably, the volume ratio of polyethylene glycol to functional agent is 1:0.01-0.05.

[0031] The present invention also discloses curcumin suppositories prepared by the above preparation method.

[0032] This invention also discloses the application of curcumin suppositories in the preparation of antitumor drugs.

[0033] This invention discloses a curcumin suppository that utilizes a polyethylene glycol (PEG) / Tween system to increase the solubility of curcumin. The high molecular weight PEG causes curcumin nanomicelles to solidify at room temperature to form a suppository, while melting at body temperature and spontaneously forming curcumin nanoparticles upon contact with water, significantly improving the solubility and bioavailability of curcumin. In the verification experiment, curcumin suppositories and curcumin oral solution were administered to rats orally and rectally at a dose of 200 mg / kg curcumin. The concentrations of curcumin and curcumin-O-glucuronide (COG), one of the main metabolites of curcumin, in plasma were determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Rat plasma samples were collected and analyzed, and the pharmacokinetic parameters of curcumin and COG in the samples were analyzed using WinNonlin software. The results showed that the curcumin suppository facilitated the attainment of peak curcumin concentration (C0.05). max The area under the blood concentration-time curve (AUC) was increased by 5.5 times and 3.5 times, respectively, compared to the curcumin oral solution treatment. This indicates that the curcumin suppository prepared in this invention is an easy-to-prepare, highly efficient, and promising curcumin dosage form that can significantly improve the bioavailability and efficacy of curcumin.

[0034] This invention utilizes a free radical polymerization reaction of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, and N-vinylacetamide to modify curcumin nanomicelles, thereby obtaining curcumin suppositories. Therefore, the curcumin suppositories prepared by this invention not only possess a high curcumin loading rate (3.54-8.97%), but also exhibit excellent cancer cell inhibition effects, with cancer cell survival rates of 71-97% after treatment with the curcumin suppositories prepared by this invention. Therefore, this invention provides a curcumin suppository with high drug loading rate and excellent inhibitory effect on cancer cell proliferation. Attached Figure Description

[0035] Figure 1 This is a morphological diagram.

[0036] Figure 2 The results show the morphological characteristics of curcumin suppositories.

[0037] Figure 3 Electron micrograph of curcumin nanoparticles in a diluted curcumin nanogel solution.

[0038] Figure 4 The results are for pharmacokinetic comparison.

[0039] Figure 5 Survival rate of MDA-MB-231 breast cancer cells.

[0040] Figure 6 Survival rate of MCF-7 breast cancer cells.

[0041] Figure 7 The survival rate of leukemia MV4-11 cells.

[0042] Figure 8 To assess the stability of curcumin suppositories. Detailed Implementation

[0043] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0044] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0045] Example 1: The preparation method of curcumin suppositories includes, Curcumin and polyethylene glycol (PEG 1500) were mixed and heated at 100°C, vortexing every 5 minutes until a clear solution was formed. Tween 20 was then added and mixed thoroughly to obtain a dark brown clear liquid. This liquid was poured into suppository molds, cooled, and then demolded to obtain curcumin suppositories. The ratio of curcumin to Tween was 1 g:10 mL; the volume ratio of Tween to polyethylene glycol was 1:7.

[0046] Example 2: The preparation method of curcumin suppositories includes, Curcumin was mixed with polyethylene glycol (PEG 1500) and heated at 100°C. The mixture was vortexed every 5 minutes until a clear solution was formed. Tween 20 was added and mixed evenly. Then, an alkenyl monomer solution was added and stirred for 3 hours. Functional agents were added and stirred for 3 hours under a nitrogen atmosphere. The reaction solution was poured into a suppository mold, cooled, and then demolded to obtain curcumin suppositories. The ratio of curcumin to Tween was 1 g:10 mL; the volume ratio of Tween to polyethylene glycol was 1:7; the alkenyl monomer solution was a mixture of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, and dimethyl sulfoxide, with a ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine of 1 mL:0.3 g and a ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether of 1 mL:0.1 g; the volume ratio of polyethylene glycol to alkenyl monomer solution was 1:0.05; the functional agents included a solution of methylenebisacrylamide, an aqueous solution of ammonium persulfate, and an aqueous solution of tetramethylethylenediamine, with the methylenebisacrylamide solution being a mixture of methylenebisacrylamide and dimethyl sulfoxide, a ratio of methylenebisacrylamide to dimethyl sulfoxide of 1 g:5 mL, the concentration of the ammonium persulfate aqueous solution being 0.2 g / mL, and the concentration of the tetramethylethylenediamine aqueous solution being 0.2 g / mL. The volume ratio of methylenebisacrylamide solution to ammonium persulfate aqueous solution was 1:0.5, the volume ratio of methylenebisacrylamide solution to tetramethylethylenediamine aqueous solution was 1:1, and the volume ratio of polyethylene glycol to functional agent was 1:0.02.

[0047] Example 3: The preparation method of curcumin suppositories is the same as in Example 2, except that the ratio of deionized water to 2-(ethoxy)ethylamine is changed to 1 mL:0.1 g.

[0048] Example 4: The preparation method of curcumin suppositories is the same as in Example 2, except that the ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is changed to 1 mL:0.02 g.

[0049] Example 5: The preparation method of curcumin suppositories is the same as in Example 2, except that the alkenyl monomer solution is replaced with a mixture of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, N-vinylacetamide and dimethyl sulfoxide, the ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine is 1 mL:0.3 g, the ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is 1 mL:0.1 g, and the ratio of dimethyl sulfoxide to N-vinylacetamide is 1 mL:0.1 g.

[0050] Example 6: The preparation method of curcumin suppositories is the same as in Example 2, except that the alkenyl monomer solution is replaced with a mixture of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, N-vinylacetamide and dimethyl sulfoxide, the ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine is 1 mL:0.3 g, the ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is 1 mL:0.1 g, and the ratio of dimethyl sulfoxide to N-vinylacetamide is 1 mL:0.02 g.

[0051] Comparative Example 1: The preparation method of curcumin suppositories is the same as in Example 2, except that the alkenyl monomer solution is replaced with a mixture of 2-(ethoxy)ethylamine and dimethyl sulfoxide, and the ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine is 1 mL:0.3 g.

[0052] Comparative Example 2: The preparation method of curcumin suppositories is the same as in Example 2, except that the alkenyl monomer solution is replaced with a mixture of ethylene glycol methyl vinyl ether and dimethyl sulfoxide, and the ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is 1 mL:0.1 g.

[0053] Comparative Example 3: The preparation method of curcumin suppositories is the same as in Example 2, except that the alkenyl monomer solution is replaced with a mixture of N-vinylacetamide and dimethyl sulfoxide, and the ratio of dimethyl sulfoxide to N-vinylacetamide is 1 mL:0.02 g.

[0054] Experimental example: 1. Morphological comparison Following the preparation method of Example 1, a dark brown clear liquid and the final prepared curcumin suppositories were obtained. The resulting dark brown clear liquid was molten curcumin nanogel. The molten curcumin nanogel was diluted with deionized water to obtain curcumin nanogel dilutions with final concentrations of 80 mg / mL, 3.2 mg / mL, 1.6 mg / mL, and 0.8 mg / mL, respectively. The morphology of the curcumin nanogel dilutions at each concentration gradient was photographed and observed.

[0055] Curcumin was diluted with dimethyl sulfoxide to obtain curcumin solutions with final concentrations of 80 mg / mL, 3.2 mg / mL, 1.6 mg / mL, and 0.8 mg / mL. The morphology of the curcumin solutions at each concentration gradient was observed by photographing.

[0056] Figure 1 The images show the morphological results of the curcumin nanogel dilution at a final concentration of 80 mg / mL, 3.6 mg / mL, 0.8 mg / mL, 8.8 mg / mL.

[0057] Figure 2 The results are for the morphological characteristics of curcumin suppositories. Figure 3 Electron micrograph of curcumin nanoparticles in a diluted curcumin nanogel solution. Figures 1 to 3 It is known that the curcumin suppository prepared by this invention greatly increases the solubility of curcumin, with a solubility of 10-200 mg / mL; by selecting a suitable polyethylene glycol / Tween system, rectal suppositories can be prepared, which is convenient for administration; and the curcumin suppository spontaneously forms curcumin nanoparticles upon contact with water, with an average particle size of 228.6±91.5 nm, which improves the bioavailability of curcumin.

[0058] 2. Pharmacokinetic Comparison Pharmacokinetic comparisons were conducted in rats using curcumin suppositories (CNG) and curcumin oral solutions (CS) prepared in Example 1, respectively. The specific experimental procedures were as follows: Sprague-Dawley rats weighing approximately 200 g were administered rectally with either the curcumin suppositories or the curcumin oral solution prepared in Example 1 at an equivalent dose of 200 mg / kg curcumin. Blood samples were collected via retro-orbital venous plexus puncture at 0 min, 15 min, 30 min, 60 min, 180 min, and 360 min after administration. All heparin-anticoagulated whole blood samples were immediately centrifuged at 1000 g for 5 minutes at 4°C. The concentrations of curcumin and curcumin-O-glucuronide (COG) were detected using liquid chromatography-tandem mass spectrometry (LC-MS / MS), and pharmacokinetic parameters were calculated using WinNonlin software based on the corresponding pharmacokinetic models. Figure 4 For pharmacokinetic comparison results, CNG-curcumin represents the curcumin concentration after administration of the curcumin suppository prepared in Example 1, CNG-COG represents the COG concentration after administration of the curcumin suppository prepared in Example 1, CS-curcumin represents the curcumin concentration after administration of the curcumin oral solution, and CS-COG represents the COG concentration after administration of the curcumin oral solution. Table 1 shows the pharmacokinetic comparison parameters, where λ Z HL-λ represents the terminal elimination rate constant. Z T represents the terminal elimination half-life. max Represents the peak time, C max Represents the peak concentration, C last AUC represents the concentration observed at the last time. 0-6h The area under the plasma concentration-time curve (AUC) represents the plasma concentration from 0 to 6 hours. INF_obs Vz_ represents the area under the blood drug concentration-time curve from 0 to infinity. F_obs Represents the apparent volume of distribution, Cl_ F_obs CNG represents apparent clearance rate, CNG represents curcumin suppositories, CS represents curcumin oral solution, and COG represents curcumin-O-glucuronide.

[0059] Table 1 Comparative parameters of curcumin pharmacokinetics parameter unit Curcumin (CNG) Curcumin (CS) Ratio CNG:CS COG (CNG) COG (CS) Ratio CNG:CS <![CDATA[λ Z ]]> 1 / min 0.0048 0.0015 3.200 0.0019 0.0048 0.396 <![CDATA[HL-λ Z ]]> min 306.9 629.8 0.487 422.4 289.6 1.459 <![CDATA[T max ]]> min 13 162 0.080 123 181 0.680 <![CDATA[C max ]]> μM 0.639 0.117 5.462 0.757 0.158 4.791 <![CDATA[C last ]]> μM 0.2837 0.0813 3.490 0.4904 0.1429 4.766 <![CDATA[AUC 0-6h ]]> min×μM 85.2 24.1 3.535 156.06 37.71 4.138 <![CDATA[AUC INF_obs ]]> min×μM 187.65 61.23 3.065 466.67 119.17 3.916 <![CDATA[Vz _F_obs ]]> L / kg 1056 7406.4 0.143 721.7 1980.3 0.364 <![CDATA[Cl _F_obs ]]> L / min / kg 3.7 9.4 0.394 1.3 9.4 0.138 Depend on Figure 4 As shown in Table 1, the curcumin suppositories prepared in this invention significantly improve bioavailability. Compared with the same dose of curcumin oral solution, the area under the plasma concentration-time curve (AUC) of the curcumin suppositories prepared in this invention is significantly higher. 0-6h Increased to 3.5 times, reaching peak concentration C maxThe curcumin absorption rate was increased by 5.5 times. The curcumin peak time of the curcumin suppository prepared in Example 1 of this invention was significantly faster than that of the curcumin oral solution, and the COG of curcumin metabolites was significantly reduced, indicating a decreased first-pass effect of curcumin. This demonstrates that the first-time delivery of curcumin via rectal suppositories not only increases its absorption but also reduces the first-pass effect, slowing down the metabolic rate of curcumin in the body.

[0060] 3. Tumor cell inhibition effect The curcumin suppositories and curcumin solutions prepared in Example 1 were diluted to final concentrations of 1 μM, 2 μM, 5 μM, 10 μM, 20 μM, 30 μM, and 50 μM, respectively, using cell culture medium. The cell culture medium was a mixture of fetal bovine serum, penicillin-streptomycin solution, and DMEM culture medium, wherein the volume of fetal bovine serum accounted for 10% of the volume of DMEM culture medium, and the volume of penicillin-streptomycin solution accounted for 1% of the volume of DMEM culture medium. Fetal bovine serum, penicillin-streptomycin solution, and DMEM culture medium were all purchased from Thermo Fisher Scientific (China) Co., Ltd. The curcumin solution was prepared by dissolving curcumin in dimethyl sulfoxide to prepare a 100 mM curcumin solution. The above solution was added to breast cancer MDA-MB-231, MCF-7, and leukemia MV4-11 cells for 72 h. After treatment, cell viability was detected by the MST method, and IC50 was calculated. 50 value.

[0061] Figure 5 For the survival rate of breast cancer MDA-MB-231 cells, Figure 6 For the survival rate of MCF-7 breast cancer cells, Figure 7 Survival rate of leukemia MV4-11 cells. Figures 5 to 7 It is evident that, compared to curcumin, the curcumin suppository prepared in this invention has a stronger inhibitory effect on tumor cell growth.

[0062] Table 2 shows the IC50 values ​​for different curcumin preparations. 50 Value. As shown in Table 2, compared with curcumin, the IC50 of the curcumin suppositories prepared in this invention is higher. 50 The value is even lower.

[0063] Table 2 IC50 values ​​of different curcumin preparations 50 value

[0064] The curcumin suppositories prepared in Examples 1-6 and Comparative Examples 1-3 were diluted to a final concentration of 5 μM using cell culture medium. The cell culture medium was a mixture of fetal bovine serum, penicillin-streptomycin solution, and DMEM culture medium, wherein the volume of fetal bovine serum accounted for 10% of the volume of DMEM culture medium, and the volume of penicillin-streptomycin solution accounted for 1% of the volume of DMEM culture medium. Fetal bovine serum, penicillin-streptomycin solution, and DMEM culture medium were all purchased from Thermo Fisher Scientific (China) Co., Ltd. The above solutions were added to MCF-7 breast cancer cells for 72 h of treatment. After treatment, cell viability was detected using the MST method. Table 3 shows the cell viability of MDA-MB-231 breast cancer cells.

[0065] Table 3. Cell survival rate (%) of MDA-MB-231 breast cancer cells.

[0066] As shown in Table 3, the curcumin suppositories prepared in Examples 2-4 of this invention exhibit better cancer cell inhibition effects than those in Example 1. This is because, in the preparation of the curcumin suppositories, Examples 2-4 additionally introduced 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether for free radical polymerization. The curcumin suppositories prepared in Example 2 exhibit better cancer cell inhibition effects than those in Examples 3 and 4, because the amounts of 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether used in the preparation of the curcumin suppositories differ. This indicates that the curcumin suppositories prepared by additionally introducing 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether for free radical polymerization have good cancer cell inhibition effects. The curcumin suppositories prepared in Example 2 exhibit better cancer cell inhibition effects than those in Comparative Examples 1 and 2, because in the preparation of the curcumin suppositories, Example 2 synergistically used 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether, while Comparative Example 1 used only 2-(ethoxy)ethylamine, and Comparative Example 2 used only ethylene glycol methyl vinyl ether. This indicates that, compared to introducing 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether alone for free radical polymerization, the curcumin suppository prepared by synergistic use of 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether has a better inhibitory effect on cancer cells.

[0067] The curcumin suppositories prepared in Examples 5-6 of this invention exhibit better cancer cell inhibition effects than those in Example 2 because N-vinylacetamide was further introduced into the preparation of the curcumin suppositories in Examples 5-6 for free radical polymerization. The cancer cell inhibition effect of the curcumin suppositories prepared in Example 5 is better than that in Example 6 because the amount of N-vinylacetamide used in the preparation of the curcumin suppositories differs. The cancer cell inhibition effect of the curcumin suppositories prepared in Example 5 is better than that in Comparative Example 3 because N-vinylacetamide was used alone in the preparation of the curcumin suppositories. This indicates that the further introduction of N-vinylacetamide into the preparation of the curcumin suppositories in this invention for free radical polymerization helps to further enhance the cancer cell inhibition effect of the curcumin suppositories.

[0068] 4. Stability of curcumin suppositories The curcumin suppositories prepared in Example 1 of this invention were treated at room temperature and 37°C for 60 days, respectively, and the curcumin concentration in the suppositories was detected on days 0, 14, 30 and 60.

[0069] Figure 8 To ensure the stability of curcumin suppositories. Figure 8 It can be seen that curcumin is stable in curcumin suppositories, and no significant change in content was observed after 60 days of storage at room temperature and 37°C.

[0070] 5. Drug loading rate of curcumin suppositories Curcumin suppositories prepared in Examples 1-6 and Comparative Examples 1-3 were collected, and their drug loading rates were determined. The specific steps are as follows: Deionized water was added to the curcumin suppositories to fully dissolve them. The resulting solution was added to an ultrafiltration centrifuge tube and centrifuged at 12000 g for 5 min at low temperature. After centrifugation, the solution in the outer tube of the ultrafiltration centrifuge tube was taken, and the curcumin concentration was determined by high-performance liquid chromatography (HPLC). The content of free drug was calculated and recorded as M1. Then, the solution in the inner tube of the ultrafiltration centrifuge tube was taken, freeze-dried, and weighed to obtain the total weight of the micelles. An equal volume of acetonitrile and a 0.5% sodium dodecyl sulfate aqueous solution were added to allow the micelles to fully dissociate. The curcumin concentration was determined by high-performance liquid chromatography (HPLC), and the content of physically loaded curcumin was calculated and recorded as M2. Drug loading rate (%) = M2 / M1 × 100%. Table 4 shows the drug loading rate (%) of the curcumin suppositories.

[0071] Table 4. Drug loading rate of curcumin suppositories (%)

[0072] As shown in Table 4, the drug loading rate of the curcumin suppositories prepared in Examples 2-4 of this invention is higher than that in Example 1. This is because, in the preparation of the curcumin suppositories, Examples 2-4 additionally introduced 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether for free radical polymerization. The drug loading rate of the curcumin suppositories prepared in Example 2 is higher than that in Examples 3 and 4. This is because the amounts of 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether used in the preparation of the curcumin suppositories are different. This indicates that the additional introduction of 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether for free radical polymerization in this invention results in a higher drug loading rate for the prepared curcumin suppositories. The drug loading rate of the curcumin suppositories prepared in Example 2 of this invention is higher than that in Comparative Examples 1 and 2. This is because, in the preparation of the curcumin suppositories, Example 2 uses 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether synergistically, while Comparative Example 1 uses only 2-(ethoxy)ethylamine, and Comparative Example 2 uses only ethylene glycol methyl vinyl ether. This indicates that, compared to introducing 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether alone for free radical polymerization, the curcumin suppository prepared by synergistic use of 2-(ethoxy)ethylamine and ethylene glycol methyl vinyl ether has a higher drug loading rate.

[0073] The drug loading rate of the curcumin suppositories prepared in Examples 5-6 of this invention is higher than that in Example 2 because N-vinylacetamide was further introduced into the preparation of the curcumin suppositories in Examples 5-6 for free radical polymerization. The drug loading rate of the curcumin suppositories prepared in Example 5 is higher than that in Example 6 because the amount of N-vinylacetamide used in the preparation of the curcumin suppositories is different. The drug loading rate of the curcumin suppositories prepared in Example 5 is higher than that in Comparative Example 3 because N-vinylacetamide was used alone in the preparation of the curcumin suppositories in Comparative Example 3. This shows that the further introduction of N-vinylacetamide into the preparation of the curcumin suppositories in this invention for free radical polymerization helps to further improve the drug loading rate of the curcumin suppositories.

[0074] The conventional operations in the operation steps of this invention are well known to those skilled in the art and will not be described in detail here.

[0075] The embodiments described above provide a detailed explanation of the technical solutions of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any changes and modifications made within the scope of the principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing a curcumin suppository, comprising: heating curcumin and polyethylene glycol at high temperature and vortexing until a clear solution is formed; adding Tween and mixing evenly to obtain a dark brown clear liquid; pouring the dark brown clear liquid into a suppository mold; and demolding after cooling to obtain the curcumin suppository; wherein the high temperature is 80-100℃; the ratio of curcumin to Tween is 1 g: 1-20 mL; the volume ratio of Tween to polyethylene glycol is 1:4-10; the solubility of curcumin in the suppository is 10-200 mg / mL; and the curcumin suppository spontaneously forms curcumin nanoparticles upon contact with water, with an average particle size of 137.1-320.1 nm.

2. The method for preparing a curcumin suppository according to claim 1, characterized in that, The preparation method of the curcumin suppository includes heating curcumin and polyethylene glycol at high temperature and vortexing until a clear solution is formed, adding Tween and mixing evenly, adding alkenyl monomer solution and stirring for 2-5 h, then adding functional agent under nitrogen atmosphere and stirring for 2-5 h, pouring the reaction solution into suppository mold, cooling and demolding to obtain curcumin suppository.

3. The method for preparing a curcumin suppository according to claim 2, characterized in that, The alkenyl monomer solution is a mixture of 2-(ethoxy)ethylamine, ethylene glycol methyl vinyl ether, and dimethyl sulfoxide.

4. The method for preparing a curcumin suppository according to claim 3, characterized in that, The ratio of dimethyl sulfoxide to 2-(ethoxy)ethylamine is 1 mL: 0.1-0.3 g.

5. The method for preparing a curcumin suppository according to claim 3, characterized in that, The ratio of dimethyl sulfoxide to ethylene glycol methyl vinyl ether is 1 mL: 0.02-0.1 g.

6. The method for preparing a curcumin suppository according to claim 2, characterized in that, The functional agents include a solution of methylenebisacrylamide, an aqueous solution of ammonium persulfate, and an aqueous solution of tetramethylethylenediamine.

7. The method for preparing a curcumin suppository according to claim 6, characterized in that, The methylenebisacrylamide solution is a mixture of methylenebisacrylamide and dimethyl sulfoxide.

8. The method for preparing a curcumin suppository according to claim 6, characterized in that, The volume ratio of the methylenebisacrylamide solution to the ammonium persulfate aqueous solution is 1:0.2-1, and the volume ratio of the methylenebisacrylamide solution to the tetramethylethylenediamine aqueous solution is 1:0.5-2.

9. Curcumin suppositories prepared by any one of the preparation methods described in claims 1-8.

10. The use of the curcumin suppository according to claim 9 in the preparation of antitumor drugs.

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