Preparation of the porous ZIF-8 and the behaviors of loading ibuprofen
-
摘要: 由于难溶性药物低的溶解度，严重限制了其口服生物利用度。对此，结合金属—有机框架材料(MOFs)具有疏水性和高比表面积的特点，以溶液共沉淀法制备的MOF多孔材料ZIF-8作为载药基底。通过改变Zn2+与2-甲基咪唑(2-Methylimidazole)的摩尔比，进而对ZIF-8的比表面积及孔径分布进行调控，然后对难溶性药物布洛芬(IBP)的负载性能进行研究。研究结果表明：当Zn2+与2-甲基咪唑的摩尔比为1∶8时，材料ZIF-8(8)具有最大的比表面积和孔体积，分别为1187 m2/g和1.183 cm3/g，其对难溶性药物布洛芬的负载量高达21.8%。且药物载体复合材料IBP-ZIF-8(8)表现出良好的体外溶出度，在pH为2.5和7.4的磷酸缓冲溶液中，其累积溶出度均为98%左右。ZIF-8(8)处理的RAW246.7细胞存活率均高达94%以上，表现出良好的生物安全性。Abstract: Oral bioavailability of poorly soluble drugs is severely limited due to their low solubility. In recent years, metal-organic framework materials (MOFs) have attracted much attention because of their hydrophobicity and high specific surface area. In this paper, the porous ZIF-8, one of MOF family materials, were prepared by solution co-precipitation method. The specific surface area and pore size distribution of ZIF-8 were optimized by changing the molar ratio of Zn2+ to 2-Methylimidazole. In addition, ZIF-8 were used as the carrier for ibuprofen (IBP), a poorly soluble drug, and its loading performance was studied in detail. The results showed that when the molar ratio of Zn2+ to 2-methylimidazole was 1∶8, ZIF-8(8) had the largest specific surface area (1187 m2/g) and pore volume (1.183 cm3/g). And the loading capacity of ZIF-8(8) on IBP was as high as 21.8%. The drug carrier composite (IBP-ZIF-8(8)) showed a well dissolution rate in vitro, and its cumulative dissolution rate was about 98% in phosphate buffer solution with pH of 2.5 and 7.4. The survival rate of RAW246.7 cells treated with IBP-ZIF-8(8) was over 94%, demonstrating satisfied biosafety. ZIF-8(8) with excellent specific surface area, pore volume, good loaded-IBP performance and biosafety has great potential applications in drug controlled-release system.
-
Key words:
- metal-organic frameworks /
- ZIF-8 /
- ibuprofen /
- poorly soluble drugs /
- oral bioavailability
-
图 1 不同ZIF-8材料的XRD衍射图(a) 和红外图谱(b)
Figure 1. XRD spectrum (a) and FTIR spectrum (b) of ZIF-8 materials
图 3 不同ZIF-8材料的N2吸脱附曲线(a)；DFT孔径曲线(b)；BJH孔径曲线(c)；HK孔径曲线(d)
Figure 3. N2 adsorption and desorption curves (a); DFT pore size curves (b); BJH pore size curves (c); HK pore size curves (d) of ZIF-8 materials
图 4 布洛芬在乙醇溶剂和不同pH下(pH=7.4；pH=2.5)的紫外吸收光谱
Figure 4. UV absorption spectra of ibuprofen in ethanol solvent and at different pH values (pH=7.4; pH=2.5)
图 5 布洛芬在在乙醇溶剂和不同pH下(pH=7.4; pH=2.5)的标准曲线
Figure 5. Standard curves of ibuprofen in ethanol solvent and at different pH values (pH=7.4; pH=2.5)
图 6 IBP与IBP-ZIF-8(8)的XRD衍射图谱(a)和IBP、IBP-ZIF-8(8)和ZIF-8(8)的TG图谱(b)
Figure 6. XRD specrum of IBP and IBP-ZIF-8(8) (a) and TG curves of IBP, IBP-ZIF-8(8) and ZIF-8(8) (b)
图 7 IBP-ZIF-8(8)在不同pH下的溶出曲线(a：pH=2.5; b：pH=7.4)
Figure 7. Dissolution curves of IBP-ZIF-8(8) at different pH values (a: pH=2.5; b: pH=7.4)
图 8 RAW246.7细胞与ZIF-8(8)共培养24 h后的细胞存活率
Figure 8. Survival rate of RAW246.7 cells co-cultured with ZIF-8(8) for 24 hours.
表 1 实验过程中使用的试剂
Table 1. Reagents used during the experiment
Name of reagents Purity Source Zinc nitrate hydrate AR Kelong Chemical Reagent Co. Ethanol AR Kelong Chemical Reagent Co. 2-Methylimidazole AR Zhenri Chemical Co. Ibuprofen (IBP) AR Solarbio Science & Technology Co. Phosphate solution AR Pricella Biotechnology Co. 
下载: 导出CSV
表 2 不同ZIF-8材料的比表面积和孔径参数
Table 2. Specific surface area and pore size parameters of ZIF-8 materials
Samples SBET/
(m2·g−1)Vmesopore/
(cm3·g−1)Vmicropore/
(cm3·g−1)ZIF-8(4) 872.033 0.199 0.615 ZIF-8(8) 1186.919 0.305 0.878 ZIF-8(12) 1078.442 0.221 0.668 Notes: SBET: Specific surface area; Vmesopore: mesopore volume; Vmicropore: micropore volume
下载: 导出CSV
表 3 不同ZIF-8材料对布洛芬的载药量
Table 3. Loading capacity of ZIF-8 material for ibuprofen
Samples Solvent Drug loading/% ZIF-8(4) ethanol 11.9 ZIF-8(8) ethanol 21.8 ZIF-8(12) ethanol 18.2
下载: 导出CSV
-
[1] BAGHEL S, CATHCART H, OREILLY N J. Polymeric amorphous solid dispersions: a review of amorphization, crystallization, stabilization, solid-State characterization, and aqueous solubilization of biopharmaceutical classification system class II drugs[J]. Journal of Pharmaceutical Sciences, 2016, 105(9): 2527-2544. doi: 10.1016/j.xphs.2015.10.008 [2] GRUET P, MAINCENT P, BERTHELOT X, et al. Bovine mastitis and intramammary drug delivery: review and perspectives[J]. Advanced Drug Delivery Reviews, 2001, 50(3): 245-259. doi: 10.1016/S0169-409X(01)00160-0 [3] LOFTSSON T, BREWSTER M E. Pharmaceutical applications of cyclodextrins: basic science and product development[J]. Journal of Pharmacy and Pharmacology, 2010, 62(11): 1607-1621. doi: 10.1111/j.2042-7158.2010.01030.x [4] KAWABATA Y, WADA K, NAKATANI M, et al. Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: basic approaches and practical applications[J]. International Journal of Pharmaceutics, 2011, 420(1): 1-10. doi: 10.1016/j.ijpharm.2011.08.032 [5] KESISOGLOU F, PANMAI S, WU Y H. Nanosizing-oral formulation development and biopharmaceutical evaluation[J]. Advanced Drug Delivery Reviews, 2007, 59(7): 631-644. doi: 10.1016/j.addr.2007.05.003 [6] SHI X J, SONG S J, DING Z J, et al. Improving the solubility, dissolution, and bioavailability of ibrutinib by preparing it in a coamorphous state with saccharin[J]. Journal of Pharmaceutical Sciences, 2019, 108(9): 3020-3028. doi: 10.1016/j.xphs.2019.04.031 [7] SANCHES B M A, FERREIRA E I. Is prodrug design an approach to increase water solubility?[J]. International Journal of Pharmaceutics, 2019, 568: 118498. doi: 10.1016/j.ijpharm.2019.118498 [8] VIYHANI K, JANNIN V, POUTON C W, et al. Colloidal aspects of dispersion and digestion of self-dispersing lipid-based formulations for poorly water-soluble drugs[J]. Advanced Drug Delivery Reviews, 2019, 142: 16-34. doi: 10.1016/j.addr.2019.01.008 [9] SONG J, WANG Y C, SONG Y L, et al. Development and characterisation of ursolic acid nanocrystals without stabiliser having improved dissolution rate and in vitro anticancer activity[J]. Aaps Pharmscitech, 2014, 15(1): 11-19. doi: 10.1208/s12249-013-0028-0 [10] CHEN S, GAO Y, LOU X C, et al. Overcoming bioavailability challenges of dasabuvir and enabling a triple-combination direct-acting antiviral HCV regimen through a salt of very weak acid for oral delivery[J]. Molecular Pharmaceutics, 2022, 19(7): 2367-2379. doi: 10.1021/acs.molpharmaceut.2c00161 [11] TANG Y, WANG Z, LI C X. Preparation of a novel amphiphilic copolymer microspheres with phenylborate moieties and its glucose-sensitive properties[J]. Chemical Journal of Chinese Universities-Chinese, 2007, 28(8): 1581-1585. [12] OU L Q, ZENG Q Y, ZHAO G W, et al. Effects of different carrier materials and preparation methods on the stability of andrographolide solid dispersions[J]. Chinese Traditional Patent Medicine, 2021, 42(12): 3117-3122. [13] YANG Y S, LI Z, ZHANG K J, et al. Preparation of water-soluble altrenogest inclusion complex with beta-cyclodextrin derivatives and in vitro sustained-release test[J]. Polymer, 2022, 249: 124803. doi: 10.1016/j.polymer.2022.124803 [14] YE Z Q, JIANG Y, LI L, et al. Rational design of MOF-based materials for next-generation rechargeable batteries[J]. Nano-Micro Letters, 2021, 13(1): 203. doi: 10.1007/s40820-021-00726-z [15] DUMAN F D, MONACO A, FOULKES R, et al. Glycopolymer-functionalized MOF-808 nanoparticles as a cancer-targeted dual drug delivery system for carboplatin and floxuridine[J]. ACS Applied Nano Materials, 2022, 5(10): 13862-13873. doi: 10.1021/acsanm.2c01632 [16] ZHANG X, PENG F, WANG D H. MOFs and MOF-derived materials for antibacterial application[J]. Journal of Functional Biomaterials, 2023, 13(4): 215. [17] 白杨, 吴宜凡, 卢洪燕等. 介孔二氧化硅和中空介孔二氧化硅载体用于提高难溶性药物溶出度的比较[J]. 沈阳药科大学学报, 2019, 36(4): 293-299.BAI Yang, WU Yifan, LU Hongyan et al. Comparison of mesoporous silica and hollow mesoporous silica carriers for enhancing the dissolution of insoluble drugs[J]. Journal of Shenyang Pharmaceutical University, 2019, 36(4): 293-299(in Chinese). [18] KIRCHON A, FENG L, DRAKE H F, et al. From fundamentals to applications: a toolbox for robust and multifunctional MOF materials[J]. Chemical Society Reviews, 2018, 47(23): 8611-8638. doi: 10.1039/C8CS00688A [19] MALEKI A, SHAHBAZI M A, ALINEZHAD V, et al. The progress and prospect of zeolitic imidazolate frameworks in cancer therapy, antibacterial activity, and biomineralization[J]. Advanced Healthcare Materials, 2020, 9(12): 2000248. doi: 10.1002/adhm.202000248 [20] KHALAF S, SHOQEIR J H, LELARIO F, et al. TiO2 and active coated glass photodegradation of ibuprofen[J]. Catalysts, 2020, 10(5): 560. doi: 10.3390/catal10050560 [21] ZAPPATERRA F, TUPINI C, SUMMA D, et al. Xylitol as a hydrophilization moiety for a biocatalytically synthesized ibuprofen prodrug[J]. International Journal of Molecular Sciences, 2022, 23(4): 2026. doi: 10.3390/ijms23042026 [22] 周佳, 孙燕燕, 温美强等. 布洛芬口服纳米乳的制备及处方优化研究[J]. 沈阳药科大学学报, 2020, 37(10): 865-871.ZHOU Jia, SUN Yanyan, WEN Meiqiang, et al. Preparation and prescription optimization of ibuprofen oral nanoemulsion[J]. Journal of Shenyang Pharmaceutical University, 2020, 37(10): 865-871(in Chinese). [23] ZHANG Y, ZHANG K, WANG Z, et al. Transcutol® P/Cremophor® EL/ethyl oleate–formulated microemulsion loaded into hyaluronic acid–based hydrogel for improved transdermal delivery and biosafety of ibuprofen[J]. AAPS PharmSciTech, 2020, 21: 1-10. doi: 10.1208/s12249-019-1542-5 [24] HANNON B A, FAIRFIELD W D, ADAMS B, et al. Use and abuse of dietary supplements in persons with diabetes[J]. Nutrition & Diabetes, 2020, 10(1): 14. [25] ZHANG T, JIN X Y, OWENS G, et al. Remediation of malachite green in wastewater by ZIF-8@Fe/Ni nanoparticles based on adsorption and reduction[J]. Journal of Colloid and Interface Science, 2021, 594: 398-408. doi: 10.1016/j.jcis.2021.03.065 -
下载:
点击查看大图
计量
- 文章访问数: 338
- HTML全文浏览量: 140
- 被引次数: 0
