An overview of dry powder inhaler production methods

Year 2025, Volume: 29 Issue: 3, 1333 - 1349, 04.06.2025

Cemre İrem Aygüler Özlem Akbal Dağıstan , Ayca Yıldız Peköz

https://doi.org/10.12991/jrespharm.1712419

Abstract

In comparison with alternative delivery strategies, pulmonary administration of drugs may provide several benefits, especially when utilizing dry powder formulations. The studies have frequently concentrated on dry powder inhalers (DPIs) due to certain pros with regard to stability, dose, and patient preference. Milling, freeze-drying, spray-drying, and electrospray are the production methods for DPIs. Conventional carrier-based DPIs and newgeneration carrier-free DPIs are two essential kinds of DPI formulations. In the marketplace today, carrier-based formulations generate the majority of DPIs. To improve the dispersibility of inhalable dry powders, formulation approaches typically involve the incorporation of micronized active pharmaceutical ingredients (APIs) with larger-sized particles, like lactose, as carriers. Nevertheless, in carrier-based formulations, the dose of drugs that could be given to patients is lower compared to carrier-free formulations. The lung deposition of the majority of carrier-based formulations is still not particularly high. Individuals who have a diagnosed allergy to lactose ought to avoid DPI products based on lactose carriers. Lactose can also interact with the functional groups of drugs or proteins since it is a reducing sugar. Furthermore, the quality and source of the lactose have been found to have a significant impact on a powder formulation's effectiveness. Carrier-free formulations seem like an advantageous choice in these situations. In this review, the formulation excipients of carrier-based and carrier-free DPIs were evaluated. Alternative delivery systems and production technologies for DPIs were also discussed.

Keywords

Carrier , dry powder , excipient , inhalation

References

• [1] Yıldız-Peköz A, Ehrhardt C. Advances in pulmonary drug delivery. Pharmaceutics. 2020;12(10):911. https://doi.org/10.3390/pharmaceutics12100911
• [2] Mehta P. Dry powder ınhalers: A focus on advancements in novel drug delivery systems. J Drug Deliv. 2016;2016:8290963. https://doi.org/10.1155/2016/8290963
• [3] Newman SP. Drug delivery to the lungs: Challenges and opportunities. Ther Deliv 2017; 8(8): 647–661. https://doi.org/10.4155/tde-2017-0037
• [4] Yurdasiper A, Arıcı M, Özyazıcı M. Nanopharmaceuticals: Application in Inhaler Systems. In: Shegokar R, Souto EB. (Eds). Emerging Nanotechnologies in Immunology: The Design, Applications and Toxicology of Nanopharmaceuticals and Nanovaccines. Elsevier, 2018, pp. 165–201. https://doi.org/10.1016/B978-0-323-40016-9.00007-5
• [5] Mishra B, Singh J. Novel drug delivery systems and significance in respiratory diseases. In: Dua K, Wadhwa R, Pont LG, Hansbro PM, Haghi M, Williams KA. (Eds). Targeting Chronic Inflammatory Lung Diseases Using Advanced Drug Delivery Systems. Academic Press, 2020, pp. 57–95. https://doi.org/10.1016/B978-0-12-820658-4.00004-2
• [6] Pilcer G, Amighi K. Formulation strategy and use of excipients in pulmonary drug delivery. Int J Pharm 2010; 392(1–2): 1–19. https://doi.org/10.1016/j.ijpharm.2010.03.017
• [7] Rogliani P, Calzetta L, Coppola A, Cavalli F, Ora J, Puxeddu E, Matera MG, Cazzola M. Optimizing drug delivery in COPD: The role of inhaler devices. Respir Med 2017; 124: 6–14. https://doi.org/10.1016/j.rmed.2017.01.006
• [8] Arıca-Yegin B. Akciğerlere Uygulanan Nano Boyutlu Taşıyıcılar. In: Zırh-Gürsoy A. (Eds). Nanofarmasötikler ve Uygulamaları. Kontrollü Salım Sistemleri Derneği Yayını, İstanbul, 2014, pp. 321-328.
• [9] Woodcock A, Beeh KM, Sagara H, Aumônier S, Addo-Yobo E, Khan J, Vestbo J, Tope H. The environmental impact of inhaled therapy: Making informed treatment choices. Eur Respir J. 2022; 60(1): 2102106. https://doi.org/10.1183/13993003.02106-2021
• [10] Sorino C, Negri S, Spanevello A, Visca D, Scichilone N. Inhalation therapy devices for the treatment of obstructive lung diseases: the history of inhalers towards the ideal inhaler. Eur J Intern Med. 2020; 75: 15–18. https://doi.org/10.1016/j.ejim.2020.02.023
• [11] de Boer AH, Hagedoorn P, Hoppentocht M, Buttini F, Grasmeijer F, Frijlink HW. Dry powder inhalation: past, present and future. Expert Opin Drug Deliv 2017; 14(4): 499–512. https://doi.org/10.1080/17425247.2016.1224846
• [12] Akdağ-Çaylı Y, Şahin S, Öner L. Kuru Toz İnhalerler: Formülasyonlar ve Aerodinamik Davranışlar. Hacettepe Univ J Fac Pharm. 2018; 38(1): 39-52.
• [13] Han X, Li D, Reyes-Ortega F, Schneider-Futschik EK. Dry powder ınhalation for lung delivery in cystic fibrosis. Pharmaceutics 2023; 15(5):1488. https://doi.org/10.3390/pharmaceutics15051488
• [14] Chaurasiya B, Zhao YY. Dry powder for pulmonary delivery: A comprehensive review. Pharmaceutics 2020;13(1):31. https://doi.org/10.3390/pharmaceutics13010031
• [15] Healy AM, Amaro MI, Paluch KJ, Tajber L. Dry powders for oral inhalation free of lactose carrier particles. Adv Drug Deliv Rev 2014; 75: 32–52. https://doi.org/10.1016/j.addr.2014.04.005
• [16] Hebbink GA, Jaspers M, Peters HJW, Dickhoff BHJ. Recent developments in lactose blend formulations for carrier-based dry powder inhalation. Adv Drug Deliv Rev 2022; 189: 114527. https://doi.org/10.1016/j.addr.2022.114527
• [17] Wong SN, Weng J, Ip I, Chen R, Lakerveld R, Telford R, Blagden N, Scowen IJ, Chow SF. Rational development of a carrier-free dry powder ınhalation formulation for respiratory viral ınfections via quality by design: A drug-drug cocrystal of favipiravir and theophylline. Pharmaceutics 2022; 14(2): 300. https://doi.org/10.3390/pharmaceutics14020300
• [18] Zillen D, Beugeling M, Hinrichs WLJ, Frijlink HW, Grasmeijer F. Natural and bioinspired excipients for dry powder inhalation formulations. Curr Opin Colloid Interface Sci 2021; 56: 101497 https://doi.org/10.1016/j.cocis.2021.101497
• [19] Karimi K, Pallagi E, Szabó-Révész P, Csóka I, Ambrus R. Development of a microparticle-based dry powder inhalation formulation of ciprofloxacin hydrochloride applying the quality by design approach. Drug Des Devel Ther 2016; 10: 3331–3343. https://doi.org/10.2147/DDDT.S116443
• [20] Ambrus R, Benke E, Farkas Á, Balásházy I, Szabó-Révész P. Novel dry powder inhaler formulation containing antibiotic using combined technology to improve aerodynamic properties. Eur J Pharm Sci. 2018; 123: 20–27. https://doi.org/10.1016/j.ejps.2018.07.030
• [21] Park H, Ha ES, Kim MS. Surface modification strategies for high-dose dry powder inhalers. J Pharm Investig 2021; 51(6): 635–668. https://doi.org/10.1007/s40005-021-00529-9
• [22] Ziaee A, Albadarin AB, Padrela L, Femmer T, O’Reilly E, Walker G. Spray drying of pharmaceuticals and biopharmaceuticals: Critical parameters and experimental process optimization approaches. Eur J Pharm Sci. 2019; 127: 300–318. https://doi.org/10.1016/j.ejps.2018.10.026
• [23] Hickey AJ, da Rocha SR. Pharmaceutical Inhalation Aerosol Technology, third ed., CRC Press, Boca Raton, Florida, 2019.
• [24] Yang MS, Kang JH, Kim DW, Park CW. Recent developments in dry powder inhalation (DPI) formulations for lung-targeted drug delivery. J Pharm Investig 2024; 54(2): 113–130. https://doi.org/10.1007/s40005-023-00635-w
• [25] Johnson KA. Preparation of peptide and protein powders for inhalation. Adv Drug Deliv Rev 1997; 26: 3–15.
• [26] Zhang Y, Mackenzie B, Koleng JJ, Maier E, Warnken ZN, Williams RO. Development of an excipient-free peptide dry powder ınhalation for the treatment of pulmonary fibrosis. Mol Pharm 2020; 17(2): 632–644. https://doi.org/10.1021/acs.molpharmaceut.9b01085
• [27] Brunaugh AD, Jan SU, Ferrati S, Smyth HDC. Excipient-free pulmonary delivery and macrophage targeting of clofazimine via air jet micronization. Mol Pharm 2017; 14(11): 4019–4031. https://doi.org/10.1021/acs.molpharmaceut.7b00690
• [28] Gaidhani KA, Harwalkar M, Bhambere D, Nirgude PS. Lyophilization/freeze drying-A review. World J Pharm Res. 2015; 4(8): 516-543.
• [29] Deepak B, Iqbal Z. Lyophilization-process and optimization for pharmaceuticals. Int J Drug Regul Aff. 2015; 3(1): 30-40.
• [30] Jain H, Bairagi A, Srivastava S, Singh SB, Mehra NK. Recent advances in the development of microparticles for pulmonary administration. Drug Discov Today. 2020; 25(10): 1865–1872. https://doi.org/10.1016/j.drudis.2020.07.018
• [31] Kasper JC, Friess W. The freezing step in lyophilization: Physico-chemical fundamentals, freezing methods and consequences on process performance and quality attributes of biopharmaceuticals. Eur J Pharm Biopharm. 2011; 78(2): 248–263. https://doi.org/10.1016/j.ejpb.2011.03.010
• [32] Snowman JW. Lyophilization. In: Goldberg E. (Eds). Handbook of Downstream Processing, Blackie Academic & Professional, London, 1997, pp. 203-234.
• [33] Malamatari M, Charisi A, Malamataris S, Kachrimanis K, Nikolakakis I. Spray drying for the preparation of nanoparticle-based drug formulations as dry powders for inhalation. Processes 2020; 8(7):788. https://doi.org/10.3390/pr8070788
• [34] Ameri M, Maa YF. Spray drying of biopharmaceuticals: Stability and process considerations. Dry Technol. 2006; 24(6): 763–768. https://doi.org/10.1080/03602550600685275
• [35] Sosnik A, Seremeta KP. Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers. Adv Colloid Interface Sci. 2015; 223: 40–54. https://doi.org/10.1016/j.cis.2015.05.003
• [36] Arpagaus C, Meuri M. Laboratory scale spray drying of inhalable particles: A review. Respir Drug Deliv. 2010; 469-476.
• [37] Sansone F, Aquino RP, Gaudio P Del, Colombo P, Russo P. Physical characteristics and aerosol performance of naringin dry powders for pulmonary delivery prepared by spray-drying. Eur J Pharm Biopharm. 2009; 72(1): 206–213. https://doi.org/10.1016/j.ejpb.2008.10.007
• [38] Arauzo B, Lopez-Mendez TB, Lobera MP, Calzada-Funes J, Pedraz JL, Santamaria J. Excipient-free inhalable microparticles of azithromycin produced by electrospray: A novel approach to direct pulmonary delivery of antibiotics. Pharmaceutics 2021; 13(12):1988. https://doi.org/10.3390/pharmaceutics13121988
• [39] Chen DR, Pui DYH. Electrospray and its medical applications. In: Marijnissen JC, Gradon L. (Eds). Nanoparticles in Medicine and Environment: Inhalation and Health Effects. Kluwer Academic Publishers, 2010, pp. 59–75. https://doi.org/10.1007/978-90-481-2632-3_4
• [40] Jahangiri A, Nokhodchi A, Asare-Addo K, Salehzadeh E, Emami S, Yaqoubi S, Hamishehkar H. Carrier-free ınhalable dry microparticles of celecoxib: Use of the electrospraying technique. Biomedicines 2023; 11(6):1747. https://doi.org/10.3390/biomedicines11061747
• [41] Faramarzi AR, Barzin J, Mobedi H, Gorji M. Polymeric pharmaceutical nanoparticles developed by electrospray. In: Ficai D, Grumezescu AM. (Eds). Nanostructures for Novel Therapy, Elsevier, 2017, pp. 137-164.
• [42] Morais AÍS, Vieira EG, Afewerki S, Sousa RB, Honorio LMC, Cambrussi ANCO, Santos JA, Bezerra RDS, Furtini JAO, Silva-Filho EC, Webster TJ, Lobo AO. Fabrication of polymeric microparticles by electrospray: The impact of experimental parameters. J Funct Biomater 2020; 11(1):4. https://doi.org/10.3390/jfb11010004
• [43] Yaqoubi S, Adibkia K, Nokhodchi A, Emami S, Alizadeh AA, Hamishehkar H, Barzegar-Jalali M. Co-electrospraying technology as a novel approach for dry powder inhalation formulation of montelukast and budesonide for pulmonary co-delivery. Int J Pharm 2020; 591: 119970 https://doi.org/10.1016/j.ijpharm.2020.119970
• [44] El-Sherbiny IM, El-Baz NM, Yacoub MH. Inhaled nano -and microparticles for drug delivery. Glob Cardiol Sci Pract 2015; 2015:2. https://doi.org/10.5339/gcsp.2015.2
• [45] Pulivendala G, Bale S, Godugu C. Inhalation of sustained release microparticles for the targeted treatment of respiratory diseases. Drug Deliv Transl Res 2020; 10(2): 339–353. https://doi.org/10.1007/s13346-019-00690-7
• [46] Willis L, Hayes D, Mansour HM. Therapeutic liposomal dry powder inhalation aerosols for targeted lung delivery. Lung 2012; 190(3): 251–262. https://doi.org/10.1007/s00408-011-9360-x
• [47] Patel K, Bothiraja C, Mali A, Kamble R. Investigation of sorafenib tosylate loaded liposomal dry powder inhaler for the treatment of non-small cell lung cancer. Particul Sci Technol. 2021; 39(8): 990–999. https://doi.org/10.1080/02726351.2021.1906367
• [48] Lee JJ, Dinh L, Park J, Khraisat R, Park JW, Jeong JK, Lee J, Kim HS, Park MS, Ahn JH, Hwang SJ. Preparation and characterization of lysozyme loaded liposomal dry powder inhalation using non-ionic surfactants. Int J Pharm. 2023; 646: 123426. https://doi.org/10.1016/j.ijpharm.2023.123426
• [49] Honmane S, Hajare A, More H, Osmani RAM, Salunkhe S. Lung delivery of nanoliposomal salbutamol sulfate dry powder inhalation for facilitated asthma therapy. J Liposome Res. 2019; 29(4): 332–342. https://doi.org/10.1080/08982104.2018.1531022
• [50] Hu Y, Li M, Zhang M, Jin Y. Inhalation treatment of idiopathic pulmonary fibrosis with curcumin large porous microparticles. Int J Pharm. 2018; 551(1–2): 212–222. https://doi.org/10.1016/j.ijpharm.2018.09.031
• [51] Mezzena M, Scalia S, Young PM, Traini D. Solid lipid budesonide microparticles for controlled release inhalation therapy. AAPS J. 2009; 11(4): 771–778. https://doi.org/10.1208/s12248-009-9148-6
• [52] Scalia S, Haghi M, Losi V, Trotta V, Young PM, Traini D. Quercetin solid lipid microparticles: A flavonoid for inhalation lung delivery. Eur J Pharm Sci. 2013; 49(2): 278–285. https://doi.org/10.1016/j.ejps.2013.03.009
• [53] Kwon YB, Kang JH, Han CS, Kim DW, Park CW. The effect of particle size and surface roughness of spray-dried bosentan microparticles on aerodynamic performance for dry powder inhalation. Pharmaceutics 2020; 12(8): 765. https://doi.org/10.3390/pharmaceutics12080765
• [54] Dolatabadi JEN, Hamishehkar H, Valizadeh H. Development of dry powder inhaler formulation loaded with alendronate solid lipid nanoparticles: Solid-state characterization and aerosol dispersion performance. Drug Dev Ind Pharm. 2015; 41(9): 1431–1437. https://doi.org/10.3109/03639045.2014.956111
• [55] Maretti E, Rustichelli C, Romagnoli M, Balducci AG, Buttini F, Sacchetti F, Leo E, Iannuccelli V. Solid Lipid Nanoparticle assemblies (SLNas) for an anti-TB inhalation treatment—A design of experiments approach to investigate the influence of pre-freezing conditions on the powder respirability. Int J Pharm. 2016; 511(1): 669–679. https://doi.org/10.1016/j.ijpharm.2016.07.062
• [56] Nemati E, Mokhtarzadeh A, Panahi-Azar V, Mohammadi A, Hamishehkar H, Mesgari-Abbasi M, Dolatabadi JEN, de la Guardia M. Ethambutol-loaded solid lipid nanoparticles as dry powder ınhalable formulation for tuberculosis therapy. AAPS PharmSciTech. 2019; 20(3):120. https://doi.org/10.1208/s12249-019-1334-y
• [57] Li YZ, Sun X, Gong T, Liu J, Zuo J, Zhang ZR. Inhalable microparticles as carriers for pulmonary delivery of thymopentin-loaded solid lipid nanoparticles. Pharm Res. 2010; 27(9): 1977–1986. https://doi.org/10.1007/s11095-010-0201-z
• [58] Schoubben A, Vivani R, Paolantoni M, Perinelli DR, Gioiello A, Macchiarulo A, Ricci M. D-leucine microparticles as an excipient to improve the aerosolization performances of dry powders for inhalation. Eur J Pharm Sci. 2019; 130: 54–64. https://doi.org/10.1016/j.ejps.2019.01.018
• [59] Rowe RC, Sheskey PJ, Quinn ME, Handbook of Pharmaceutical Excipients, sixth ed., RPS Publishing, UK, USA 2009.
• [60] Rahimpour Y, Kouhsoltani M, Hamishehkar H. Alternative carriers in dry powder inhaler formulations. Drug Discov Today. 2014; 19(5): 618–626. https://doi.org/10.1016/j.drudis.2013.11.013
• [61] Harjunen P, Lankinen T, Salonen H, Lehto VP, Järvinen K. Effects of carriers and storage of formulation on the lung deposition of a hydrophobic and hydrophilic drug from a DPI. Int J Pharm. 2003; 263(1–2): 151–163. https://doi.org/10.1016/S0378-5173(03)00357-0
• [62] Kaialy W, Nokhodchi A. Dry powder inhalers: Physicochemical and aerosolization properties of several size-fractions of a promising alterative carrier, freeze-dried mannitol. Eur J Pharm Sci. 2015; 68: 56–67. https://doi.org/10.1016/j.ejps.2014.12.005
• [63] Lechanteur A, Evrard B. Influence of composition and spray-drying process parameters on carrier-free DPI properties and behaviors in the lung: A review. Pharmaceutics 2020; 12(1):55. https://doi.org/10.3390/pharmaceutics12010055
• [64] Ungaro F, d’Emmanuele di Villa Bianca R, Giovino C, Miro A, Sorrentino R, Quaglia F, La Rotonda MI. Insulin-loaded PLGA/cyclodextrin large porous particles with improved aerosolization properties: In vivo deposition and hypoglycaemic activity after delivery to rat lungs. J Control Release. 2009; 135(1): 25–34. https://doi.org/10.1016/j.jconrel.2008.12.011
• [65] Shiehzadeh F, Tafaghodi M, Laal-Dehghani M, Mashhoori F, Fazly Bazzaz BS, Imenshahidi M. Preparation and characterization of a dry powder inhaler composed of PLGA large porous particles encapsulating gentamicin sulfate. Adv Pharm Bull. 2019; 9(2): 255–261. https://doi.org/10.15171/apb.2019.029
• [66] Arora S, Mahajan RR, Kushwah V, Baradia D, Misra A, Jain S. Development of voriconazole loaded large porous particles for inhalation delivery: Effect of surface forces on aerosolisation performance, assessment of in vitro safety potential and uptake by macrophages. RSC Adv. 2015; 5(48): 38030–38043. https://doi.org/10.1039/c5ra00248f
• [67] Debnath SK, Saisivam S, Debanth M, Omri A. Development and evaluation of chitosan nanoparticles based dry powder inhalation formulations of prothionamide. PLoS One. 2018; 13(1):e0190976. https://doi.org/10.1371/journal.pone.0190976
• [68] Benke E, Winter C, Szabó-Révész P, Roblegg E, Ambrus R. The effect of ethanol on the habit and in vitro aerodynamic results of dry powder inhalation formulations containing ciprofloxacin hydrochloride. Asian J Pharm Sci. 2021; 16(4): 471–482. https://doi.org/10.1016/j.ajps.2021.04.003
• [69] Benke E, Farkas Á, Balásházy I, Szabó-Révész P, Ambrus R. Stability test of novel combined formulated dry powder inhalation system containing antibiotic: physical characterization and in vitro–in silico lung deposition results. Drug Dev Ind Pharm. 2019; 45(8): 1369–1378. https://doi.org/10.1080/03639045.2019.1620268
• [70] Alhajj N, O’Reilly NJ, Cathcart H. Leucine as an excipient in spray dried powder for inhalation. Drug Discov Today. 2021; 26(10): 2384–2396. https://doi.org/10.1016/j.drudis.2021.04.009
• [71] Barazesh A, Gilani K, Rouini M, Barghi MA. Effect of pH and leucine concentration on aerosolization properties of carrier-free formulations of levofloxacin. Eur J Pharm Sci. 2018; 118: 13–23. https://doi.org/10.1016/j.ejps.2018.03.002
• [72] Nguyen TT, Yi EJ, Hwang KM, Cho CH, Park CW, Kim JY, Rhee YS, Park ES. Formulation and evaluation of carrier-free dry powder inhaler containing sildenafil. Drug Deliv Transl Res. 2019; 9(1): 319–333. https://doi.org/10.1007/s13346-018-0586-5
• [73] Nolan LM, Tajber L, McDonald BF, Barham AS, Corrigan OI, Healy AM. Excipient-free nanoporous microparticles of budesonide for pulmonary delivery. Eur J Pharm Sci. 2009; 37(5): 593–602. https://doi.org/10.1016/j.ejps.2009.05.007
• [74] Healy AM, McDonald BF, Tajber L, Corrigan OI. Characterisation of excipient-free nanoporous microparticles (NPMPs) of bendroflumethiazide. Eur J Pharm Biopharm. 2008; 69(3): 1182–1186. https://doi.org/10.1016/j.ejpb.2008.04.020
• [75] Chang RYK, Chan HK. Advancements in particle engineering for ınhalation delivery of small molecules and biotherapeutics. Pharm Res. 2022; 39(12): 3047–3061. https://doi.org/10.1007/s11095-022-03363-2
• [76] Fulford B, Mezzi K, Aumônier S, Finkbeiner M. Carbon footprints and life cycle assessments of ınhalers: A review of published evidence. Sustainability (Switzerland). 2022; 14(12):7106. https://doi.org/10.3390/su14127106
• [77] Telko MJ, Hickey AJ. Dry powder ınhaler formulation. Respir Care. 2005; 50(9): 1209–1227.
• [78] Mahar R, Chakraborty A, Nainwal N, Bahuguna R, Sajwan M, Jakhmola V. Application of PLGA as a biodegradable and biocompatible polymer for pulmonary delivery of drugs. AAPS PharmSciTech. 2023; 24(1):39. https://doi.org/10.1208/s12249-023-02502-1