反溶剂共沉淀技术制备氟苯尼考固体分散体

doi:10.11843/j.issn.0366-6964.2021.010.024

摘要/Abstract

摘要： 本文旨在通过制备氟苯尼考无定形固体分散体（amorphous solid dispersion，ASD）提高其溶解度和生物利用度。选用醋酸羟丙基甲基纤维素琥珀酸酯（hydroxypropyl methyl cellulose acetate succinate，HPMCAS-MF）为载体，利用反溶剂共沉淀法制备氟苯尼考无定形固体分散体，利用X-射线衍射、热分析及扫描电镜对ASD进行表征，并通过测定溶出度和药物代谢动力学对其体内外释药进行研究。结果显示，当氟苯尼考与载体的比例为5：5时形成固体分散体，该固体分散体无氟苯尼考的晶体衍射峰，无氟苯尼考的特定熔点峰，扫描电镜结果未见氟苯尼考ASD表面光滑的晶体形态，而是显示疏松多孔结构，表面积增大，且使氟苯尼考的饱和溶解度提高了4.8倍，相对生物利用度提高了约37.2%，该固体分散体在3个月内稳定性良好。综上表明，利用共沉淀法制备的新型氟苯尼考固体分散体稳定性良好，可有效提高氟苯尼考溶解度和生物利用度。

关键词: 氟苯尼考, 无定形固体分散体, 溶解度, 共沉淀法

Abstract: This article aims to prepare florfenicol amorphous solid dispersion (ASD) to improve its solubility and bioavailability. The florfenicol ASD was prepared by antisolvent coprecipitation method with hydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF) as carrier. The ASD was characterized by X-ray diffraction, thermal analysis and scanning electron microscopy. The in vitro and in vivo release of florfenicol was studied by dissolution and pharmacokinetics. When the ratio of florfenicol to carrier was 5:5, a solid dispersion was formed. The results showed that there was no crystal diffraction peak of florfenicol and no specific melting point peak of florfenicol. The SEM results showed that the surface of florfenicol ASD was loose and porous, and increased the surface area, and the saturated solubility of florfenicol increased by 4.8 times, and the relative bioavailability increased by 37.2%, and no drug crystal peak appeared in the solid dispersion within 3 months. The results showed that the new solid dispersion of florfenicol prepared by co-precipitation method has good stability and could effectively improve the solubility and bioavailability of florfenicol.

Key words: florfenicol, amorphous solid dispersion, solubility, co-precipitation method

中图分类号:

刘连超, 王灵灵, 张雨晴, 李金辉, 赵兴华, 何欣. 反溶剂共沉淀技术制备氟苯尼考固体分散体[J]. 畜牧兽医学报, 2021, 52(10): 2934-2943.

LIU Lianchao, WANG Lingling, ZHANG Yuqing, LI Jinhui, ZHAO Xinghua, HE Xin. Preparation of Florfenicol Solid Dispersion by Antisolvent Co-precipitation Technology[J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(10): 2934-2943.

参考文献 38

[1]	杨锐, 李旭廷, 李金良, 等. 甘草提取物对氟苯尼考在鸡体内药动学和生物利用度的影响[J]. 中国兽医学报, 2019, 39(11):2222-2226.YANG R, LI X T, LI J L, et al. Effect of licorice extract on pharmacokinetics and bioavailability of florfenicol in chicken[J]. Chinese Journal of Veterinary Science, 2019, 39(11):2222-2226. (in Chinese)
[2]	RATTANAPANADDA P, KUO H C, VICKROY T W, et al. In vitro and in vivo synergistic effects of florfenicol and thiamphenicol in combination against swine Actinobacillus pleuropneumoniae and Pasteurella multocida[J]. Front Microbiol, 2019, 10:2430.
[3]	孙继超, 陈晨, 张东辉, 等. 氟苯尼考的研究进展[J]. 江苏农业科学, 2020, 48(20):31-36.SUN J C, CHEN C, ZHANG D H, et al. Research progress of florfenicol[J]. Jiangsu Agricultural Sciences, 2020, 48(20):31-36. (in Chinese)
[4]	张春辉, 邢广旭, 胡骁飞, 等. 动物专用药物氟苯尼考的研究进展[J]. 中兽医医药杂志, 2019, 38(5):95-98.ZHANG C H, XING G X, HU X F, et al. Reviewed on the animal medicine florfenicol[J]. Journal of Traditional Chinese Veterinary Medicine, 2019, 38(5):95-98. (in Chinese)
[5]	FANG Y Q, LI S Q, YE L J, et al. Increased bioaffinity and anti-inflammatory activity of florfenicol nanocrystals by wet grinding method[J]. J Microencapsul, 2020, 37(2):109-120.
[6]	FAN G Q, ZHANG L, SHEN Y, et al. Comparative muscle irritation and pharmacokinetics of florfenicol-hydroxypropyl-β-cyclodextrin inclusion complex freeze-dried powder injection and florfenicol commercial injection in beagle dogs[J]. Sci Rep, 2019, 9(1):16739.
[7]	李胜利, 刘保光, 赵晓宁, 等. 多种高分子材料制备氟苯尼考固体分散体及其对比分析[J]. 中国农业科技导报, 2018, 20(3):139-144.LI S L, LIU B G, ZHAO X N, et al. Preparation and comparative analysis of florfenicol solid dispersions using different polymers for pharmaceuticals[J]. Journal of Agricultural Science and Technology, 2018, 20(3):139-144. (in Chinese)
[8]	刘子瑶, 黄春梅, 许颖, 等. 姜黄素固体分散体在猪体内的比较药动学研究[J]. 畜牧兽医学报, 2020, 51(11):2858-2866.LIU Z Y, HUANG C M, XU Y, et al. Pharmacokinetics of curcumin solid dispersion in piglets[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(11):2858-2866. (in Chinese)
[9]	王宝贵, 王璐婷, 杨胜利. 热熔挤出技术制备氟苯尼考固体分散体的研究[J]. 浙江农业科学, 2020, 61(11):2392-2396.WANG B G, WANG L T, YANG S L. Study on preparation of solid dispersions containing florfenicol by hot-melt extrusion[J]. Journal of Zhejiang Agricultural Sciences, 2020, 61(11):2392-2396. (in Chinese)
[10]	孟凡亮. 氟苯尼考对鸡胚胎发育及雏鸡免疫功能的影响研究[D]. 泰安:山东农业大学, 2020.MENG F L. Effects of florfenicol on embryonic development and immune function of chicken[D]. Taian:Shandong Agricultural University, 2020. (in Chinese)
[11]	刘一欢, 顾王文, 陆振举, 等. 基于HPMCAS载体的依非韦伦固体分散体溶出模式研究[J]. 中国现代应用药学, 2020, 37(9):1096-1101.LIU Y H, GU W W, LU Z J, et al. Study on the dissolution model of efavirenz in solid dispersion based on HPMCAS carrier[J]. Chinese Journal of Modern Applied Pharmacy, 2020, 37(9):1096-1101. (in Chinese)
[12]	MONSCHKE M, WAGNER K G. Impact of HPMCAS on the dissolution performance of polyvinyl alcohol celecoxib amorphous solid dispersions[J]. Pharmaceutics, 2020, 12(6):541.
[13]	ZHANG Q X, ZHAO Y N, ZHAO Y P, et al. Effect of HPMCAS on recrystallization inhibition of nimodipine solid dispersions prepared by hot-melt extrusion and dissolution enhancement of nimodipine tablets[J]. Colloids Surf B Biointerfaces, 2018, 172:118-126.
[14]	CURATOLO W, NIGHTINGALE J A, HERBIG S M. Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu[J]. Pharm Res, 2009, 26(6):1419-1431.
[15]	HAWARE R V, VINJAMURI B P, GAVIREDDI M, et al. Physical properties and solubility studies of Nifedipine-PEG 1450/HPMCAS-HF solid dispersions[J]. Pharm Dev Technol, 2019, 24(5):550-559.
[16]	LIU M Z, WANG X, WANG Y P, et al. Controlled stimulation-burst targeted release by pH-sensitive HPMCAS/theophylline composite nanofibers fabricated through electrospinning[J]. J Appl Polym Sci, 2020, 137(7):48383.
[17]	SARABU S, KALLAKUNTA V R, BANDARI S, et al. Hypromellose acetate succinate based amorphous solid dispersions via hot melt extrusion:Effect of drug physicochemical properties[J]. Carbohydr Polym, 2020, 233:115828.
[18]	LIANG Q, WANG Y R, DENG Y Y. Effect of HPMCAS/curcumin amorphous solid dispersion in enhancing dissolution and chemical stability of curcumin[J]. China Journal of Chinese Materia Medica, 2019, 44(15):3305-3311.
[19]	李天舒, 高崇凯, 易军, 等. 利用Box-Behnken效应面法优化氟苯尼考纳米混悬剂处方[J]. 中国兽医科学, 2020, 50(2):247-253.LI T S, GAO C K, YI J, et al. Optimizations of the formulation of florfenicol nanosuspension by Box-Behnken design response surface method[J]. Chinese Veterinary Science, 2020, 50(2):247-253. (in Chinese)
[20]	王志霞, 黎欣, 武梦茹, 等. 基于制剂新技术提高氟苯尼考溶解性的研究进展[J]. 动物医学进展, 2020, 41(10):91-95.WANG Z X, LI X, WU M R, et al. Progress on improving solubility of florfenicol based on new preparation technology[J]. Progress in Veterinary Medicine, 2020, 41(10):91-95. (in Chinese)
[21]	张瑞丽, 李志中, 孙春华, 等. 氟苯尼考环糊精包合物的药物代谢动力学研究[J]. 中国兽药杂志, 2020, 54(7):61-66.ZHANG R L, LI Z Z, SUN C H, et al. The pharmacokinetics of florfenicol cyclodextrin inclusion complex[J]. Chinese Journal of Veterinary Drug, 2020, 54(7):61-66. (in Chinese)
[22]	梁立杰, 黎键业, 许颖, 等. 氟苯尼考缓释颗粒的制备及体外释放特性[J]. 华南农业大学学报, 2020, 41(4):1-7.LIANG L J, LI J Y, XU Y, et al. Preparation and in vitro release characteristics of florfenicol sustained-release granules[J]. Journal of South China Agricultural University, 2020, 41(4):1-7. (in Chinese)
[23]	马可, 张勇军, 邓桦, 等. 氟苯尼考-β-环糊精包合物的制备与结构表征[J]. 中国抗生素杂志, 2018, 43(2):223-227.MA K, ZHANG Y J, DENG H, et al. Preparation and characterization of florfenicol-β-cyclodextrin inclusion complex[J]. Chinese Journal of Antibiotics, 2018, 43(2):223-227. (in Chinese)
[24]	娄雅婧. 氟苯尼考新固体形态的开发与评价研究[D]. 天津:天津大学, 2018.LOU Y Q. Development and evaluation of new solid forms of florfenicol[D]. Tianjin:Tianjin University, 2018. (in Chinese)
[25]	瑞普(天津)生物药业有限公司. 一种无定形氟苯尼考及其制备方法:中国, 201410155935. 7[P]. 2014-04-17.Ruipu (Tianjin) Biopharmaceutical Co., Ltd. Amorphous florfenicol and preparation method thereof:CN, 201410155935. 7[P]. 2014-04-17. (in Chinese)
[26]	曹航. HPMC修饰的氟苯尼考微晶体的制备、表征及其药动学研究[D]. 雅安:四川农业大学, 2014.CAO H. Preparation, charaderization and pharmacokinetics of florfenicol microcrystal modified by HPMC[D]. Ya'an:Sichuan Agricultural University, 2014. (in Chinese)
[27]	JADHAV P, GOKARNA V, DESHPANDE V, et al. Bioavailability enhancement of olmesartan medoxomil using hot-melt extrusion:In-Silico, In-Vitro, and in-vivo evaluation[J]. AAPS PharmSciTech, 2020, 21(7):254.
[28]	RAGHVENDRA C, NIMISHA S, APOORVA S. Enhancement of dissolution rate of quercetin using solid dispersion approach:In vitro and in vivo evaluation[J]. Nanosci Nanotechnol Asia, 2020, 10(3):330-349.
[29]	刘畅. 氟苯尼考速崩片的制备及药代动力学研究[D]. 雅安:四川农业大学, 2018.LIU C. A dissertation submitted to Sichuan agricultural university in partial fulfillment of the requirements for the professional degree of master of veterinary medicine[D]. Ya'an:Sichuan Agricultural University, 2018. (in Chinese)
[30]	MA S Y, SHANG X J. Preparation and characterization of florfenicol-polyethyleneglycol 4000 Solid dispersions with improved solubility[J]. Asian Journal of Chemistry, 2012, 24(7):3059-3063.
[31]	XU Y, WEN X, FENG X, et al. Preparation, characterization, and pharmacokinetics in swine of a florfenicol enteric formulation prepared using hot-melt extrusion technology[J]. J Vet Pharmacol Ther, 2018, 41(4):572-580.
[32]	闫浩松. 氟苯尼考新型粉剂的制备及其质量评价[D]. 开封:河南大学, 2016.YAN H S. Preparation of new type of florfenicol powder and its quality evaluation[D]. Kaifeng:Henan University, 2016. (in Chinese)
[33]	张彩丽, 李晓琴, 张亦斌, 等. 热熔挤出技术提高药物溶解性能的机理及应用[J]. 成都大学学报:自然科学版, 2017, 36(4):369-372, 381.ZHANG C L, LI X Q, ZHANG Y B, et al. Mechanism and application of hot melt extrusion technology to improve drug dissolution properties[J]. Journal of Chengdu University:Natural Science Edition, 2017, 36(4):369-372, 381. (in Chinese)
[34]	傅行弟. 熔融法制备非诺贝特缓释胶囊的处方工艺研究[J]. 安徽医药, 2016, 20(5):852-855.FU X D. Formulation and preparation process investigation on fenofibrate sustain-released capsule prepared by melting method[J]. Anhui Medical and Pharmaceutical Journal, 2016, 20(5):852-855. (in Chinese)
[35]	谭佳威, 孙如煜, 曾滟棱, 等. 固体分散技术在制剂领域的研究进展[J]. 药物评价研究, 2017, 40(8):1182-1188.TAN J W, SUN R Y, ZENG Y L, et al. Research progress on solid dispersion technique in preparative field[J]. Drug Evaluation Research, 2017, 40(8):1182-1188. (in Chinese)
[36]	CHOW S F, SUN C C, CHOW A H L. Assessment of the relative performance of a confined impinging jets mixer and a multi-inlet vortex mixer for curcumin nanoparticle production[J]. Eur J Pharm Biopharm, 2014, 88(2):462-471.
[37]	李金丰, 陆振举, 顾王文, 等. 依非韦伦固体分散体的制备及其体内外评价[J]. 中国医药工业杂志, 2019, 50(5):530-538.LI J F, LU Z J, GU W W, et al. Preparation of efavirenz solid dispersion and its in vitro and in vivo evaluation[J]. Chinese Journal of Pharmaceuticals, 2019, 50(5):530-538. (in Chinese)
[38]	蒋一秀, 李尚民, 范建华, 等. 枯草芽孢杆菌对如皋黄鸡肠道pH值、养分表观消化率及粪便中氨气和硫化氢释放量的影响[J]. 中国家禽, 2018, 40(19):32-35.JIANG Y X, LI S M, FAN J H, et al. Effect of Bacillus subtilis on pH value of intestinal tract, utilization efficiency of nutrient, ammonia and hydrogen sulfide released from faeces of rugao yellow chicken[J]. China Poultry, 2018, 40(19):32-35. (in Chinese)