张芯蕊，张 欣，关 健，毛世瑞

（沈阳药科大学 药学院, 辽宁 沈阳 110016）

DOI：3732/j.issn.1008-5548.2022.01.012

收稿日期： 2021-09-01，修回日期：2021-10-09，在线出版时间：2021-11-26。

基金项目：国家重点研发计划项目，编号：2020YFE0201700。

第一作者简介：张芯蕊(1998—)，女，硕士研究生，研究方向为干粉吸入剂。E-mail: 335368627@qq.com。

通信作者简介：毛世瑞(1969—)，女，教授，博士生导师，研究方向为生物可降解高分子聚合物作为药物载体、肺部吸入、鼻黏膜递药

摘要：综述喷雾干燥的原理；粒子组分重分布、固化及固化后形态的改变等形成过程；喷雾干燥工艺对粒子性质的影响；空气动力学直径、密度、表面疏水处理等提高干粉吸入剂肺部沉积的粒子工程策略。认为喷雾干燥在肺部给药方面的主要优势是通过操纵和控制各种参数实现对颗粒特性的优化；结合粒子工程技术与合适的赋形剂，可以获得理想的喷雾干燥颗粒，使其最大限度地沉积在肺部靶向部位；通过优化颗粒空气动力学直径、降低颗粒密度以及对微粒进行表面疏水处理可以弥补喷雾干燥微粒在粉末流动性、分散性以及药物稳定性等方面的缺点。

关键词：粒子工程；喷雾干燥；干粉吸入剂；肺部递送

Abstract：The principle of spray drying, the formation process of particle composition redistribution, solidification and morphology change after solidification, effect of spray drying process on particle properties, and the particle engineering strategies to improve lung deposition of dry powder inhalations, such as aerodynamic diameter, density andsurface hydrophobic treatment were reviewed. It is considered that the main advantage of spray drying in pulmonary drug delivery is to optimize particle properties by manipulating and controlling various parameters, and combined with particle engineering technology and appropriate excipients, ideal spray drying particles can be obtained to maximize the deposition in the lung target site. Optimization of particle aerodynamic diameter, reduction of particle density and surface hydrophobic treatment of particles can make up the disadvantages of spray drying particles in powder fluidity, dispersion and drug stability.

Keywords：particle engineering; spray drying; dry powder inhaler; pulmonary delivery

参考文献（References）：

[1]KADOTA K, SOSNOWSKI T, TOBITA S, et al.A particle technology approach toward designing dry-powder inhaler formulations for personalized medicine in respiratory diseases[J].Advanced Powder Technology, 2020, 31(1): 219-226.

[2]HEALY A, AMARO M, PALUCH K, et al.Dry powders for oral inhalation free of lactose carrier particles[J].Advanced Drug Delivery Reviews, 2014, 75: 32-52.

[3]MOMIN M A M, TUCKER I G, DAS S C.High dose dry powder inhalers to overcome the challenges of tuberculosis treatment[J].International Journal of Pharmaceutics, 2018, 550: 398-417.

[4]PILCER G, AMIGHI K.Formulation strategy and use of excipients in pulmonary drug delivery[J].International Journal of Pharmaceutics, 2010, 392(1/2): 1-19.

[5]OGI T, NANDIYANTO A B D, OKUYAMA K.Nanostructuring strategies in functional fine-particle synthesis towards resource and energy saving applications[J].Advanced Powder Technology, 2014, 25(1): 3-17.

[6]OKUYAMA K, ABDULLAH M, LENGGORO I W, et al.Preparation of functional nanostructured particles by spray drying[J].Advanced Powder Technology, 2006, 17(6): 587-611.

[7]VEHRING R.Pharmaceutical particle engineering via spray drying[J].Pharmaceutical Research, 2008, 25(5): 999-1022.

[8]薛峰.喷雾干燥微胶囊化中的玻璃体形成[J].食品科学, 1999(4): 4-6.

[9]ROOS Y.Melting and glass transitions of low molecular weight carbohydrates[J].Carbohydrate Research, 1993, 238: 39-48.

[10]黄立新, 周瑞君, MUJUMDAR A S.喷雾干燥过程中产品玻璃化温度转变和质量控制[J].林产化学与工业, 2007, 27(1): 43-46.

[11]NANDIYANTO A B D, OKUYAMA K.Progress in developing spray-drying methods for the production of controlled morphology particles: from the nanometer to submicrometer size ranges[J].Advanced Powder Technology, 2011, 22(1): 1-19.

[12]VEHRING R, FOSS W R, LECHUGA-BALLESTEROS D.Particle formation in spray drying[J].Journal of Aerosol Science, 2007, 38(7): 728-746.

[13]TSAPIS N, BENNETT D, JACKSON B, et al.Trojan particles: large porous carriers of nanoparticles for drug delivery[J].Proceedings of the National Academy of Sciences of the United States of America, 2002, 99(19): 12001-12005.

[14]WEERS J, TARARA T.The pulmo Sphere platform for pulmonary drug delivery[J].Therapeutic Delivery, 2014, 5(3): 277-295.

[15]BORAEY M A, VEHRING R.Diffusion controlled formation of microparticles[J].Journal of Aerosol Science, 2014, 67: 131-143.

[16]WEERS J G, MILLER D P.Formulation design of dry powders for inhalation[J].Journal of Pharmaceutical Sciences, 2015, 104(10): 3259-3288.

[17]GAC J, GRADON L.A distributed parameter model for the spray drying of multicomponent droplets with a crust formation[J].Advanced Powder Technology, 2013, 24(1): 324-330.

[18]ALHAJJA N, O’REILLY N J, CATHCART H.Designing enhanced spray dried particles for inhalation: a review of the impact of excipients and processing parameters on particle properties[J].Powder Technology, 2021, 384: 313-331.

[19]BALDELLI A, POWER R M, MILES R E H, et al.Effect of crystallization kinetics on the properties of spray dried microparticles[J].Aerosol Science and Technology, 2016, 50(7): 693-704.

[20]VICENTE J, PINTO J, MENEZES J, et al.Fundamental analysis of particle formation in spray drying[J].Powder Technology, 2013, 247: 1-7.

[21]BALDELLI A, BORAEY M A, NOBES D S, et al.Analysis of the particle formation process of structured microparticles[J].Molecular Pharmaceutics, 2015, 12(8): 2562-2573.

[22]BUCHI.Mini Spray Dryer B-290(小型喷雾干燥仪)世界最领先的喷雾干燥研发解决方案[EB/ON].[2021-08-21]https://assets.buchi.com/image/upload/v1605791199/pdf/Brochures/PB_11592735_B-290_zh.pdf.

[23]CHAN HK, CHEW N Y K.Novel alternative methods for the delivery of drugs for the treatment of asthma[J].Advanced Drug Delivery Reviews, 2003, 55(7): 793-805.

[24]HANCOCK B C, SHAMBLIN S L, ZOGRAFI G.Molecular mobility of amorphous pharmaceutical solids below their glass transition temperatures[J].Pharmaceutical research, 1995, 12(6): 799-806.

[25]ZHANG X, GUAN J, NI R, et al.Preparation and solidification of redispersiblenanosuspensions[J].Journal of Pharmaceutical Sciences, 2014, 103(7): 2166-2176.

[26]GRADON L, SOSNOWSKI T R.Formation of particles for dry powder inhalers[J].Advanced Powder Technology, 2014, 25(1): 43-55.

[27]PILCER G, AMIGHI K.Formulation strategy and use of excipients in pulmonary drug delivery[J].International Journal of Pharmaceutics, 2010, 392(1/2): 1-19.

[28]HASSAN M S, LAU R W M.Effect of particle shape on dry particle inhalation: study of flowability, aerosolization, and deposition properties[J].AAPS Pharm Sci Tech, 2009, 10(4): 1252-1262.

[29]MAA Y F, NGUYEN P A, SIT K, et al.Spray-drying performance of a bench-top spray dryer for protein aerosol powder preparation[J].Biotechnology and Bioengineering, 1998, 60(3): 301-309.

[30]HEALY A M, AMARO M I, PALUCH K J, et al.Dry powders for oral inhalation free of lactose carrier particles[J].Advanced Drug Delivery Reviews, 2014, 75: 32-52.

[31]EDWARDS D A, HANES J, CAPONETTI G, et al.Large porous particles for pulmonary drug delivery[J].Science, 1997, 276(5320): 1868-1872.

[32]FRENCH D L, EDWARDS D A, NIVEN R W.The influence of formulation on emission, deaggregation and deposition of dry powders for inhalation[J].Journal of Aerosol Science, 1996, 27(5): 769-783.

[33]VANBEVER R, MINTZES J D, WANG J, et al.Formulation and physical characterization of large porous particles for inhalation[J].Pharmaceutical Research, 1999, 16(11): 1735-1742.

[34]DELLAMARY L A, TARARA T E, SMITH D J, et al.Hollow porous particles in metered dose inhalers[J].Pharmaceutical Research, 2000, 17(2): 168-174.

[35]GELLER D E, KONSTAN M W, SMITH J, et al.Novel tobramycin inhalation powder in cystic fibrosis subjects: pharmacokinetics and safety[J].Pediatric Pulmonology, 2007, 42(4): 307-313.

[36]STASS H, NAGELSCHMITZ J, WILLMANN S, et al.Inhalation of a dry powder ciprofloxacin formulation in healthy subjects: a phase istudy[J].Clinical Drug Investigation, 2013, 33(6): 419-427.

[37]PARLATI C, COLOMBO P, BUTTINI F, et al.Pulmonary spray dried powders of tobramycin containing sodium stearate to improve aerosolization efficiency[J].Pharmaceutical Research, 2009, 26(5): 1084-1092.

[38]BRUNAUGH A, SMYTH H.Formulation techniques for high dose dry powders[J].International Journal of Pharmaceutics, 2018, 547(1/2): 489-498.

[39]FERDYNAND M, NOKHODCHI A.Co-spraying of carriers(mannitol-lactose)as a method to improve aerosolization performance of salbutamol sulfate dry powder inhaler[J].Drug Delivery and Translational Research, 2020, 10(5): 1418-1427.

[40]ALHAJJ N, O'REILLY N J, CATHCART H.Leucine as an excipient in spray dried powder for inhalation[J].Drug Discovery Today, 2021, 26(10): 2384-2396.

[41]ORDOUBADI M, GREGSON F, WANG H, et al.On the particle formation of leucine in spray drying of inhalable microparticles[J].International Journal of Pharmaceutics, 2021, 592: 120102.

[42]MOMIN M, RANGNEKAR B, SINHA S, et al.Inhalable dry powder of bedaquiline for pulmonary tuberculosis: in vitro physicochemical characterization, antimicrobial activity and safety studies[J].Pharmaceutics, 2019, 11(10): 502.

[43]LI L, SUN S, PARUMASIVAM T, et al.L-leucine as an excipient against moisture on in vitro aerosolization performances of highly hygroscopic spray-dried powders[J].European Journal of Pharmaceutics and Biopharmaceutics, 2016, 102: 132-141.

[44]SHETTY N, PARK H, ZEMLYANOV D, et al.Influence of excipients on physical and aerosolization stability of spray dried high-dose powder formulations for inhalation[J].International Journal of Pharmaceutics, 2018, 544(1): 222-234.

[45]SIBUM I, HAGEDOORN P, FRIJLINK H, et al.Characterization and formulation of isoniazid for high-dose dry powder inhalation[J].Pharmaceutics, 2019, 233(11): 1-15.

[46]MOMIN M, SINHA S, TUCKER I, et al.Dry powder formulation of kanamycin with enhanced aerosolization efficiency for drug-resistant tuberculosis[J].International Journal of Pharmaceutics, 2017, 528(1/2): 107-117.

[47]MANGAL S, NIE H, XU R, et al.Physico-chemical properties, aerosolization and dissolution of co-spray dried azithromycin particles with l-leucine for inhalation[J].Pharm Res, 2018, 35(2): 28.

[48]SIBUM I, HAGEDOORN P, KLUITMAN M P G, et al.Dispersibilityand storage stability optimization of high dose isoniazid dry powder inhalation formulations with l-leucine or trileucine[J].Pharmaceutics, 2020, 12(1).

[49]MOMIN M, TUCKER I, DOYLE C, et al.Co-spray drying of hygroscopic kanamycin with the hydrophobic drug rifampicin to improve the aerosolization of kanamycin powder for treating respiratory infections[J].International Journal of Pharmaceutics, 2018, 541(1/2): 26-36.

[50]ZHOU Q, LOH Z, YU J, et al.How much surface coating of hydrophobic azithromycin is sufficient to prevent moisture-induced decrease in aerosolisation of hygroscopic amorphous colistin powder[J].AAPS JOURNAL, 2016, 18(5): 1213-1224.

[51]ZHOU Q T, GENGENBACH T, DENMAN J A, et al.Synergistic antibiotic combination powders of colistin and rifampicin provide high aerosolization efficiency and moisture protection[J].The AAPS Journal, 2014, 16(1): 37-47.

[52]GLISKI J, CHAVEPEYER G, PLATTEN J-K.Surface properties of aqueous solutions of L-leucine[J].Biophysical Chemistry, 2000, 84(2): 99-103.

[53]FENG A L, BORAEY M A, GWIN M A, et al.Mechanistic models facilitate efficient development of leucine containing microparticles for pulmonary drug delivery[J].International Journal of Pharmaceutics, 2011, 409(1): 156-163.

[54]LI L, LEUNG S S Y, GENGENBACH T, et al.Investigation of L-leucine in reducing the moisture-induced deterioration of spray-dried salbutamol sulfate power for inhalation[J].International Journal of Pharmaceutics, 2017, 530: 30-39.

[55]YU J, CHAN H-K, GENGENBACH T, et al.Protection of hydrophobic amino acids against moisture-induced deterioration in the aerosolization performance of highly hygroscopic spray-dried powders[J].European Journal of Pharmaceutics and Biopharmaceutics, 2017, 119: 224-234.

[56]KEENER C R, FULLERTON G D, CAMERON I L, et al.Solution nonideality related to solute molecular characteristics of amino acids[J].Biophysical Journal, 1995, 68(1): 291-302.

[57]KYTE J, DOOLITTLE R F.A simple method for displaying the hydropathic character of a protein[J].Journal of Molecular Biology, 1982, 157(1): 105-132.

[58]CHANG R Y K, CHEN L, CHEN D, et al.Overcoming challenges for development of amorphous powders for inhalation[J].Expert Opinion on Drug Delivery, 2020, 17(11): 1583-1595.

[59]D Z, M B, WLJ H, et al.Natural and bioinspired excipients for dry powder inhalation formulations[J/ON].Current Opinion in Colloid & Interface Science, 2021, 56: 101497[2021-08-27]http://dx.doi.org/10.1016/j.cocis.2021.101497.

[60]SHUR J, PRICE R, LEWIS D, et al.From single excipients to dual excipient platforms in dry powder inhaler products[J].International Journal of Pharmaceutics, 2016, 514(2): 374-383.

[61]MANGAL S, PARK H, NOUR R, et al.Correlations between surface composition and aerosolization of jet-milled dry powder inhaler formulations with pharmaceutical lubricants[J].International Journal of Pharmaceutics, 2019, 568:118504.

[62]YU J, ROMEO M C, CAVALLARO A A, et al.Protective effect of sodium stearate on the moisture-induced deterioration of hygroscopic spray-dried powders[J].International Journal of Pharmaceutics, 2018, 541(1/2): 11-18.

[63]LEE H J, BERGEN P J, BULITTA J B, et al.Synergistic activity of colistin and rifampin combination against multidrug-resistant Acinetobacter baumannii in an in vitro pharmacokinetic/pharmacodynamic model[J].Antimicrobial Agents and Chemotherapy, 2013, 57(8): 3738-3745.