赵彩凤,王麟奇,王荣荣,董春林,吕立勋
ZHAO Caifeng,WANG Linqi,WANG Rongrong,DONG Chunlin,LYU Lixun

• 1:华北理工大学药学院

摘要(Abstract)：

目的 优化阿奇霉素羧甲基壳聚糖微球的处方工艺，对其进行表征和质量评价。方法 采用乳化交联法制备阿奇霉素羧甲基壳聚糖微球；在单因素试验的基础上，采用星点设计-效应面法优化其处方工艺；采用红外光谱分析法(fourier transform infrared spectrum, FTIR)、X-射线衍射法(X-ray diffraction, XRD)和扫描电镜对其结构形态进行分析；采用透析法考察其体外释放行为；通过测定微球在模拟唾液中的释放度评价其掩味能力。结果 最优处方工艺为油水体积比4.5,载体质量浓度为36 g·L~(-1),固化时间为2.8 h,制得的微球包封率为(86.32±1.52)%,载药量为(12.08±0.14)%;微球表面光滑圆整，分布均匀；FTIR和XRD结果均证实阿奇霉素被包裹于羧甲基壳聚糖中；微球在pH 6.8磷酸盐缓冲液中8 h稳定释放；在模拟唾液中30 s的释放浓度低于其苦味阈值。结论 此制备工艺可行，制得的微球载药量和包封率较高，释药稳定，口感适宜。
Objective To optimize the formulation of azithromycin carboxymethyl chitosan microspheres, to characterize their morphological structure and evaluate their quality.Methods The microspheres were prepared by emulsion cross-linking method.Based on the single-factor experiment, the preparation process was optimized by the central composite design-response surface method.The structure and morphology were characterized by Fourier transform infrared spectrum(FTIR),X-ray diffraction(XRD)and scanning electron microscopy.The release behaviors of microspheres in vitro were investigated by dialysis method.The taste-masking effect was evaluated by measuring the release of microspheres in simulated saliva.Results The optimum formulation of microspheres was as follows: oil-water volume ratio was 4.5,carrier concentration was 36 g·L~(-1),crosslinking time was 2.8 h.The drug loading and encapsulation efficiency of microspheres were(12.08±0.14)% and(86.32±1.52)%.The surface of the microspheres was smooth, round and distributed evenly.Both the results of FTIR and XRD confirmed that azithromycin was encapsulated in carboxymethyl chitosan.The microspheres were released stably in pH 6.8 phosphate buffer for 8 h, and the release concentration in simulated saliva for 30 s was less than the bitterness threshold.Conclusion The preparation process is feasible, the microspheres exhibit high drug loading and encapsulation efficiency, which release drugs stably and have a suitable taste.

关键词(KeyWords)： 阿奇霉素;羧甲基壳聚糖;微球;掩味;响应面分析法
azithromycin;carboxymethyl chitosan;microspheres;taste masking;response surface methodology

Abstract:

Keywords:

基金项目(Foundation):

作者(Author): 赵彩凤,王麟奇,王荣荣,董春林,吕立勋
ZHAO Caifeng,WANG Linqi,WANG Rongrong,DONG Chunlin,LYU Lixun

DOI: 10.14066/j.cnki.cn21-1349/r.2021.0254

参考文献(References)：

• [1] TANG H,WANG L J,JIN X.Pharmacokinetics of azithromycin in Beagle dogs giving different dosing regimens[J].Journal of Shenyang Pharmaceutical University(沈阳药科大学学报),2016,33(12):991-995.
• [2] HUANG R,WANG T,YANG Q,et al.Characterization of taste-masking dry emulsion of azithromycin by in vitro and in vivo evaluation[J].Acta Pharmaceutica Sinica(药学学报),2017,52(5):795-801.
• [3] GANDHI R,KAUL C L,PANCHAGNULA R.Pharmacokinetic evaluation of an azithromycin controlled release dosage form in healthy human volunteers:a single dose study[J].Int J Pharm,2004,270(1/2):1-8.
• [4] CHEN X,LU A,WANG X Y,et al.Analysis of technical difficulties and new strategies of oral liquid pharmaceutical preparation for children[J].Acta Pharmaceutica Sinica(药学学报),2021,56(1):130-137.
• [5] LV B,WANG B B,YANG G B,et al.Advances in pharmaceutical polymers for drug taste masking[J].Journal of International Pharmaceutical Research(国际药学研究杂志),2020,47(11):922-927.
• [6] FAISAL W,FARAG F,ABDELLATIF A H,et al.Taste masking approaches for medicines[J].Curr Drug Deliv,2018,15(2):167-185.
• [7] LIU L,LV Q,ZHANG Q Y,et al.Preparation of carboxymethyl chitosan microspheres and their application in hemostasis[J].Disaster Med Public Health Prep,2017,11(6):660-667.
• [8] SHARIATINIA Z.Carboxymethyl chitosan:Properties and biomedical applications[J].Int J Biol Macromol,2018,120(Pt B):1406-1419.
• [9] QIANG L,QING H,QIN Y Z,et al.Development of ligustrazine hydrochloride carboxymethyl chitosan and collagen microspheres:Formulation optimization,characterization,and in vitro release[J].Bioengineered,2017,8(1):55-60.
• [10] LIU S Y,BAI X H,DONG L J,et al.Formulation optimization and in vitro release of puerarin carboxymethylchitosan microspheres[J].Chinese Journal of Pharmaceuticals(中国医药工业杂志),2016,47(3):299-304.
• [11] YANG Q R,CHEN X,SHAO Z Z.Preparation of natural polyelectrolytical chitosan/carboxymethyl chitosan complex membrane[J].Acta Chimica Sinica(化学学报),2005(4):259-262,255.
• [12] LIU Z B,WANG C Y,LIU Y F,et al.Cefepime loaded O-carboxymethyl chitosan microspheres with sustained bactericidal activity and enhanced biocompatibility[J].J Biomater Sci Polym Ed,2017,28(1):79-92.
• [13] GUAN J,XU H X,HUANG Y F,et al.Natural polymer electroactive hydrogel—soybean protein/carboxymethylchitosan system[J].Acta Chimica Sinica(化学学报),2010,68(1):89-94.
• [14] PEIN M,PREIS M,ECKERT C,et al.Taste-masking assessment of solid oral dosage forms-a critical review[J].Int J Pharm,2014,465(1/2):239-254.
• [15] TUNG N T,TRAN C S,NGUYEN T L,et al.Formulation and biopharmaceutical evaluation of bitter taste masking microparticles containing azithromycin loaded in dispersible tablets[J].Eur J Pharm Biopharm,2018,126:187-200.
• [16] BORA D,BORUDE P,BHISE K.Taste masking by spray-drying technique[J].AAPS PharmSciTech,2008,9(4):1159-1164.
• [17] YU H F.Study on optimization of preparationand formulation of chitosan microspheres(壳聚糖微球制备及工艺处方优化的研究)[D].Qingdao:Qingdao University of Science and technology,2014.
• [18] Chinese Pharmacopoeia Commission.Chinese Pharmacopoeia:Part 4(中华人民共和国药典：四部)[M].Beijing:China Medical Science Press,2020:474-475.
• [19] ZHANG D T.Preparation process optimization of possolonazole oral suspension by central composite design-response surface methodology[J].Journal of Shenyang Pharmaceutical University(沈阳药科大学学报),2019,36(8):655-661,698.
• [20] LI L,NING W F,WANG Q,et al.Preparation and in vitro drug release of resveratrol-loaded chitosan modified-hydrogel[J].Journal of Shenyang Pharmaceutical University(沈阳药科大学学报),2019,36(8):647-654,715.