替米考星肠道定位制剂的制备、体外释放度考察及表征鉴定

doi:10.16431/j.cnki.1671-7236.2024.05.034

摘要/Abstract

摘要： 【目的】采用固体分散体技术制备替米考星肠溶制剂,提高替米考星在酸中的稳定性,使其在小肠定位释放,提高替米考星的溶解速率和生物利用度,为该药的新剂型开发和临床应用提供理论参考。【方法】采用丙烯酸树脂Eudragit L100和聚乙烯吡咯烷酮(PVP)组成二元载体,采用共沉淀法制备肠道pH触发定位释放型制剂。以体外累积溶解度为评价指标,采用正交试验研究最佳制备条件,并选择X-射线衍射法、傅里叶变换红外光谱法和扫描电镜法鉴定物相。【结果】最佳的替米考星固体分散体肠溶制剂制备工艺是联合载体Eudragit L100∶PVP=10∶1、药载比为1∶2,搅拌时间为2 h,固化时间为12 h,该制剂在酸性介质中2 h溶出量＜10%,在pH 6.8的缓冲溶液中2 min内溶出度为75.02%,10 min时完全溶解,大大提高了替米考星的溶解速度。X-射线衍射分析显示,固体分散体在17°和23°衍射强度高于替米考星原料药;傅里叶变换红外光谱显示,替米考星固体分散体在1 593和1 457 cm^-1尖锐吸收峰消失;扫描电镜图中可看出替米考星均匀地分散在载体中,表明替米考星固体分散体的形成。【结论】本研究选用联合载体成功制备替米考星固体分散体肠溶制剂,其在酸中稳定,在pH 6.8缓冲液中有较好的溶出度。

关键词: 替米考星; 肠道定位制剂; 固体分散体; 溶出度; 表征鉴定

Abstract: 【Objective】 The experiment was aimed to prepare enteric formulations of temicoxacin using solid dispersion technology,improve its stability in acid,enable its targeted release in small intestine,improve its dissolution rate and bioavailability,and provide theoretical references for the development and clinical application of new dosage forms of the drug.【Method】 Acrylic resin Eudragit L100 and polyvinylpyrrolidone (PVP) were used to form a binary carrier,and the intestinal pH-triggered localized release formulation was prepared by the co-precipitation method.With in vitro cumulative solubility as the evaluation index,the optimal preparation conditions were screened by orthogonal test,and X-ray diffraction,Fourier infrared spectroscopy and scanning electron microscopy were used for the identification of the physical phase.【Result】 The optimal preparation process of tilmicosin solid dispersion enteric formulation was Eudragit L100∶PVP= 10∶1,drug-carrying ratio of 1∶2,stirring time of 2 h,curing time of 12 h.The dissolution of this formulation was ＜10% in an acidic environment for 2 h,and the degree of solubility reached 75.02% in buffer solution at pH 6.8 for 2 min,and it was completely dissolved in 10 min,which significantly improved the dissolution rate of tilmicosin.The dissolution rate of tilmicosin was significantly improved.X-ray diffraction result showed that the diffraction intensity of the solid dispersion at 17°and 23°was higher than that of tilmicosin API.Fourier infrared spectroscopy result showed that the sharp absorption peaks of solid dispersion of tilmicosin at 1 593 and 1 457 cm^-1 were disappeared.Scanning electron microscopy diagrams showed that tilmicosin had been uniformly dispersed in the carrier,the solid dispersion of tilmicosin was formed.【Conclusion】 Tilmicosin solid dispersion enteric formulation was prepared successfully by choosing the combined carrier,which was stable in acid and dissolved in pH 6.8 buffer with a good dissolution degree.

Key words: tilmicosin; enteric-coated formulation; solid dispersion; dissolution; phase identification

中图分类号:

S859.5^＋3

刘栩沂, 陈芷欣, 王鸿鑫, 叶钰莹, 韩梓杰, 张楠, 张德显, 邓桦, 杨鸿. 替米考星肠道定位制剂的制备、体外释放度考察及表征鉴定[J]. 中国畜牧兽医, 2024, 51(5): 2132-2142.

LIU Xuyi, CHEN Zhixin, WANG Hongxin, YE Yuying, HAN Zijie, ZHANG Nan, ZHANG Dexian, DENG Hua, YANG Hong. Preparation, in vitro Release,and Phase Identification of an Enteric-located Formulation of Tilmicosin[J]. China Animal Husbandry and Veterinary Medicine, 2024, 51(5): 2132-2142.

参考文献

[1] LUO W,QIN H,CHEN D,et al.The dose regimen formulation of tilmicosin against Lawsonia intracellularis in pigs by pharmacokinetic-pharmacodynamic (PK-PD) model[J].Microbial Pathogenesis,2020,147:104389.
[2] 封会贤.替米考星的最新研究进展[J].今日畜牧兽医,2018,34(11):10. FENG H X.Latest research progress on tilmicosin[J].Today Animal Husbandry and Veterinary Medicine,2018,34(11):10.(in Chinese)
[3] 刘金环,张珊玲,宋玮,等.槲皮素-替米考星混合物纳米粒的制备及对金黄色葡萄球菌小菌落变异株抗菌活性研究[J].中国畜牧兽医,2022,49(4):1470-1478. LIU J H,ZHANG S L,SONG W,et al.Preparation of quercetin-tilmicosin mixture nanoparticles and its antibacterial activity against small colony variant strains of Staphylococcus aureus[J].China Animal Husbandry & Veterinary Medicine,2022,49(4):1470-1478.(in Chinese)
[4] 刘子卿,熊威振,任豆豆,等.冀南地区滑液支原体分离鉴定及耐药性分析[J].中国畜牧兽医,2023,50(10):4270-4278. LIU Z Q,XIONG W Z,REN D D,et al.Isolation,identification and drug resistance analysis of Mycoplasma synoviae in the Southern region of Hebei province[J].China Animal Husbandry & Veterinary Medicine,2023,50(10):4270-4278.(in Chinese)
[5] 江海洋,沈建忠,胡顶飞.兽用抗菌药物替米考星[J].中国兽药杂志,2002,36(8):28-31. JIANG H Y,SHEN J Z,HU D F.Veterinary antibacterial drug tilmicosin[J].Chinese Journal of Veterinary Drug,2002,36(8):28-31.(in Chinese)
[6] 汪燕,张铎,宋亮,等.替米考星新剂型的运用研究进展[J].中国畜禽种业,2019,1:50-51. WANG Y,ZHANG D,SONG L,et al.Progress of research on the use of new dosage forms of tilmicosin[J].The Chinese Livestock and Poultry Breeding,2019,1:50-51.(in Chinese)
[7] XIONG J,ZHU Q,ZHAO Y,et al.Tilmicosin enteric granules and premix to pigs:Antimicrobial susceptibility testing and comparative pharmacokinetics[J].Journal of Veterinary Pharmacology and Therapeutics,2019,42(3):336-345.
[8] BHUJBAL S V,MITRA B,JAIN U,et al.Pharmaceutical amorphous solid dispersion:A review of manufacturing strategies[J].Acta Pharmaceutica Sinica B,2021,11(8):2505-2536.
[9] FRANCO P,DE MARCO I.Eudragit:A novel carrier for controlled drug delivery in supercritical antisolvent coprecipitation[J].Polymers,2020,12(1):234.
[10] BARBOSA J A C,Al-KAURAISHI M M,SMITH A M,et al.Achieving gastroresistance without coating:Formulation of capsule shells from enteric polymers[J].European Journal of Pharmaceutics and Biopharmaceutics,2019,144:174-179.
[11] 中国兽药典委员会.中华人民共和国兽药典(2015年版)一部[M].北京:中国农业出版社,2016. CHINESE COMMITTEE OF VETERINARY PHARMACOPOEIA.Veterinary Pharmacopoeia of the People's Republic of China (2015 ed.) Part Ⅰ[M].Beijing:China Agriculture Press,2016.(in Chinese)
[12] 方亮.药剂学[M].9版.北京:人民卫生出版社,2023. FANG L.Pharmaceutics[M].9th ed.Beijing:People's Medical Publishing House,2023.(in Chinese)
[13] 梅丽,金方.固体分散体表征手段的研究进展[J].中国医药工业杂志,2014,45(8):782-788. MEI L,JIN F.Advances in characterization methods of solid dispersion[J].Chinese Journal of Pharmaceuticals,2014,45(8):782-788.(in Chinese)
[14] MALKAWI R,MALKAWI W I,AL-MAHMOUD Y,et al.Current trends on solid dispersions:Past,present,and future[J].Advances in Pharmacological and Pharmaceutical Sciences,2022,2022:5916013.
[15] 曾庆云,祝婧云,赵国巍,等.固体分散体中药物分散状态测定方法的研究进展[J].中成药,2019,41(1):146-150. ZENG Q Y,ZHU J Y,ZHAO G W,et al.Advances in methods for determining the dispersion state of drugs in solid dispersions[J].Chinese Traditional Patent Medicine,2019,41(1):146-150.(in Chinese)
[16] 苏静,丁润峰.关于替米考星临床应用的体会[J].当代畜牧,2015,36:60-61. SU J,DING R F.Experiences on the clinical use of tilmicosin[J].Contemporary Animal Husbandry,2015,36:60-61.(in Chinese)
[17] 刘桂兰,刘爱玲,鲍恩东.口服不同剂型替米考星在鸡体内相对生物等效性研究[J].畜牧与兽医,2009,41(4):14-18. LIU G L,LIU A L,BAO E D.Relative bioequivalence of tilmicosin (powder or liquid) oral formulations in chickens[J].Animal Husbandry & Veterinary Medicine,2009,41(4):14-18.(in Chinese)
[18] 田凯,赵宝凯,闫琰.口服肠溶制剂在兽药领域中的应用前景[J].中国兽药杂志,2023,57(2):66-72. TIAN K,ZHAO B K,YAN Y.Application prospects of oral enteric-coated preparations in the field of veterinary medicine[J].Chinese Journal of Veterinary Drug,2023,57(2):66-72.(in Chinese)
[19] 梁劲康,吴志玲,黎乃添,等.替米考星微囊的体外释放特性考察[J].中国兽药杂志,2017,51(5):41-47. LIANG J K,WU Z L,LI N T,et al.Study on in vitro release behavior of tilmicosin microcapsules[J].Chinese Journal of Veterinary Drug,2017,51(5):41-47.(in Chinese)
[20] 王加才,王成森,朱术会,等.替米考星纳米乳对人工感染鸡毒支原体病的治疗效果研究[J].中国家禽,2021,43(9):44-48. WANG J C,WANG C S,ZHU S H,et al.Therapeutic effect of tilmicosin nanoemulsion on artificiaol infection Mycoplasma gallisepticum[J].China Poultry,2021,43(9):44-48.(in Chinese)
[21] WEN J,GAO X,ZHANG Q,et al.Optimization of tilmicosin-loaded nanostructured lipid carriers using orthogonal design for overcoming oral administration obstacle[J].Pharmaceutics,2021,13(3):303.
[22] JELI AC'G D.Thermal stability of amorphous solid dispersions[J].Molecules,2021,26(1):238.
[23] KAUSHIK R,BUDHWAR V,KAUSHIK D.An overview on recent patents and technologies on solid dispersion[J].Recent Patents on Drug Delivery & Formulation,2020,14(1):63-74.
[24] 李敏,程富胜,郭丽华,等.不同工艺制备的替米考星颗粒体外释放度研究[J].动物医学进展,2023,44(2):61-66. LI M,CHENG F S,GUO L H,et al.Study on in vitro dissolution of tilmicosin granules with different preparation processes[J]. Progress in Veterinary Medicine,2023,44(2):61-66.(in Chinese)
[25] TEKADE A R,YADAV J N.A review on solid dispersion and carriers used therein for solubility enhancement of poorly water soluble drugs[J]. Advanced Pharmaceutical Bulletin,2020,10(3):359-369.
[26] QIN Y,XIAO C,LI X,et al.Enteric polymer-based amorphous solid dispersions enhance oral absorption of the weakly basic drug nintedanib via stabilization of supersaturation[J].Pharmaceutics,2022,14(9):1830.
[27] LIU X,MA X,KUN E,et al.Influence of lidocaine forms (salt vs.freebase) on properties of drug-eudragit^® L100-55 extrudates prepared by reactive melt extrusion[J]. International Journal of Pharmaceutics,2018,547(1-2):291-302.
[28] 蒋婷,郑玲利,袁明勇,等.阿折地平肠溶固体分散体的制备及质量评价[J].中国药房,2021,32(15):1862-1867. JIANG T,ZHENG L L,YUAN M Y,et al.Preparation and quality evaluation of azelnidipine enteric solid dispersion[J]. China Pharmacy,2021,32(15):1862-1867.(in Chinese)
[29] HERING I,EILEBRECHT E,PARNHAM M J,et al.Evaluation of potential environmental toxicity of polymeric nanomaterials and surfactants[J].Environmental Toxicology Pharmacology,2020,76:103353.
[30] VARUM F J,MERCHANT H A,GOYANES A,et al.Accelerating the dissolution of enteric coatings in the upper small intestine:Evolution of a novel pH 5.6 bicarbonate buffer system to assess drug release[J]. International Journal of Pharmaceutics,2014,468(1-2):172-177.
[31] 韩萌萌,李沙沙,孙朋超,等.替米考星肠溶微丸的制备及其评价[J].中国兽药杂志,2014,48(2):34-38. HAN M M,LI S S,SUN P C,et al.Preparation and evaluation of tilmicosin enteric coated pellets[J]. Chinese Journal of Veterinary Drug,2014,48(2):34-38.(in Chinese)
[32] 付亭亭,左文宝,郭珏铄,等.固体分散体的释药机制及其物理稳定性研究进展[J].中国新药杂志,2020,29(3):275-280. FU T T,ZUO W B,GUO Y S,et al.Research advances in dissolution mechanism and physical stability of solid dispersions[J]. Chinese Journal of New Drugs,2020,29(3):275-280.(in Chinese)
[33] 蔡萍,欧丽泉,赵国巍,等.载体材料对固体分散体溶出行为的影响及机制研究进展[J].中国新药杂志,2021,30(17):1600-1604. CAI P,OU L Q,ZHAO G W,et al.Research progress in the influence of carrier materials on the dissolution behavior of solid dispersion and its mechanism[J].Chinese Journal of New Drugs,2021,30(17):1600-1604.(in Chinese)
[34] 聂结华,马艳芝,张志远,等.提高伊维菌素水溶性方法的研究进展[J].中国畜牧兽医,2023,50(10):4292-4300. NIE J H,MA Y Z,ZHANG Z Y,et al.Research progress on methods for improving the water solubility of ivermectin[J].China Animal Husbandry & Veterinary Medicine,2023,50(10):4292-4300.(in Chinese)
[35] YU J Y,KIM J A,JOUNG H J,et al.Preparation and characterization of curcumin solid dispersion using HPMC[J]. Journal of Food Science,2020,85(11):3866-3873.
[36] COLOMBO M,DE LIMA MELCHIADES G,MICHELS L R,et al.Solid dispersion of kaempferol:Formulation development,characterization,and oral bioavailability assessment[J]. AAPS PharmSciTech,2019,20(3):106.
[37] 石佳,康帅,张南平,等.茺蔚子的性状和显微鉴定研究与数字化表征[J].药物分析杂志,2021,41(8):1306-1315. SHI J,KANG S,ZHANG N P,et al.Study on the macroscopic and microscopic identification of Leonuri fructus[J].Chinese Journal of Pharmaceutical Analysis,2021,41(8):1306-1315.(in Chinese)
[38] THAKRAL N K,ZANON R L,KELLY R C,et al.Applications of powder X-ray diffraction in small molecule pharmaceuticals:Achievements and aspirations[J]. Journal of Pharmaceutical Science,2018,107(12):2969-2982.
[39] BENMORE C J,BENMORE S R,EDWARDS A D,et al.A high energy X-ray diffraction study of amorphous indomethacin[J]. Journal of Pharmaceutical of Science,2022,111(3):818-824.
[40] 吕彪,刘三侠,孙雪峰,等.替米考星固体分散体的制备及质量评价[J].畜牧与兽医,2015,47(9):68-71. LYU B,LIU S X,SUN X F,et al.Preparation and quality evaluation of solid dispersions of tilmicosin[J].Animal Husbandry & Veterinary Medicine,2015,47(9):68-71.(in Chinese)
[41] 伍涛,唐达.肠溶缓释型替米考星固体分散体的制备、鉴定及体外释放度评价[J].甘肃农业大学学报,2021,56(3):30-36. WU T,TANG D.Preparation and identification of enteric-coated sustained-release solid dispersions of tilmicosin and evaluation of their release degree[J].Journal of Gansu Agricultural University,2021,56(3):30-36.(in Chinese)
[42] 巴娟,张勇军,邓桦,等.替米考星固体分散体的制备与物相鉴定[J].中国兽药杂志,2019,53(1):44-49. BA J,ZHANG Y J,DENG H,et al.Preparation and phase identification of tilmicsosin solid dispersion[J].Chinese Journal of Veterinary Drug,2019,53(1):44-49.(in Chinese)
[43] 巴娟.替米考星固体分散体的制备及在猪体内的药动学研究[D].佛山:佛山科学技术学院,2019. BA J.Preparation of tilmicosin solid dispersion and the pharmacokinetics in pigs[D].Foshan:Foshan University,2019.(in Chinese)