Enhancement of inhaled micronized powder flow properties for accurate capsules filling

Dry powder inhalerCapsule fillingLung deliveryAdhesive mixtureInhalation powderInterparticle interaction forces; dry powder inhaler; capsule filling; lung delivery; adhesive mixture; inhalation powder; interparticle interaction forces

Abstract :

[en] Particle engineering holds significant promise in developing high-performance inhaled powders. The spray-drying technology leads to the optimization of particle properties, enhancing aerosolization capabilities. However, the development of such inhalation powders introduces challenges related to cohesive forces due to, among others, the small particle size. Our study aims to find an easy industrial method for improving powder flow properties to facilitate the handling of these powders, especially in the context of capsules or reservoir filling. To achieve this, we focus on adhesive blends of micronized spray-dried powder, which includes budesonide and formoterol, with coarse lactose excipient. It is intended to develop a homogeneous blend without overly strong interparticular interactions that could potentially compromise the final pulmonary deposition of micronized powders. Two lactose grades, namely Inhalac 70 and Inhalac 230, were tested in various proportions with spray-dried powder. For both lactose grades, the 50:50 mixture demonstrated homogeneity over 8 weeks, exhibiting no signs of segregation. Importantly, the forces within the blend enable optimal aerosolization, as similar performance has been observed compared to spray-dried powder alone. Subsequently, the improvement in flowability, leading to improved reproducibility in the capsule filling process, was evaluated using an industrial prototype filler (Drum TT). While achieving uniform capsule mass remained challenging with the cohesive spray-dried powder alone, the 50:50 mixtures induced compliant capsule filling. Moreover, impaction tests demonstrated comparable in vitro lung deposition compared to manually filled capsules. We further explored the impact of inhaler device resistance and airflow conditions during the impaction assay on aerosolization properties. Our research revealed the feasibility of blending micronized powder with lactose to facilitate the handling of this powder during industrial processes without compromising aerodynamic performance. Moving forward, these formulations exhibit potential for scalable industrial applications in pulmonary drug delivery.

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Gresse, Eva ; Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)

Rousseau, Justine

Akdim, Myriam

Du Bois, Audrey

Lechanteur, Anna ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique

Evrard, Brigitte ; Université de Liège - ULiège > Département de pharmacie > Pharmacie galénique

Language :

English

Title :

Enhancement of inhaled micronized powder flow properties for accurate capsules filling

Publication date :

27 February 2024

Journal title :

Powder Technology

ISSN :

0032-5910

eISSN :

1873-328X

Publisher :

Elsevier BV

Issue :

119576

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.elsevier.com/content/article/PII:S0032591024002183?httpAccept=text/xml

Available on ORBi :

since 30 March 2024

Statistics

Number of views

32 (11 by ULiège)

Number of downloads

80 (9 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenAlex citations

Bibliography

Shahin, H.I., Chablani, L., A comprehensive overview of dry powder inhalers for pulmonary drug delivery: challenges, advances, optimization techniques, and applications. J. Drug Deliv. Sci. Technol., 84, 2023, 10.1016/j.jddst.2023.104553.
Zellnitz, S., Renner, N., Cui, Y., Scherlieb, R., Sommerfeld, M., Steckel, H., Urbanetz, N., The importance of interactions between carrier and drug particles for the application in dry powder inhalers. Antonyuk, S., (eds.) Particles in Contact, 2019, Springer International Publishing, Kaiserslautern, 457–516, 10.1007/978-3-030-15899-6.
Ye, Y., Ma, Y., Zhu, J., The future of dry powder inhaled therapy: promising or discouraging for systemic disorders?. Int. J. Pharm., 614, 2022, 10.1016/j.ijpharm.2022.121457.
Ceschan, N.E., Bucalá, V., Ramírez-Rigo, M.V., Levofloxacin dry powder inhaler for high dose delivery. Powder Technol., 432, 2024, 10.1016/j.powtec.2023.119168.
Hebbink, G.A., Jaspers, M., Peters, H.J.W., Dickhoff, B.H.J., Recent developments in lactose blend formulations for carrier-based dry powder inhalation. Adv. Drug Deliv. Rev., 189, 2022, 10.1016/j.addr.2022.114527.
Karra, N., Swindle, E.J., Morgan, H., Drug delivery for traditional and emerging airway models. Organs-on-a-Chip, 1, 2019, 10.1016/j.ooc.2020.100002.
Spahn, J.E., Zhang, F., Smyth, H.D.C., Mixing of dry powders for inhalation: a review. Int. J. Pharm., 619, 2022, 10.1016/j.ijpharm.2022.121736.
Mehta, P., Imagine the superiority of dry powder inhalers from carrier engineering. J. Drug Deliv. 2018 (2018), 1–19, 10.1155/2018/5635010.
Shah, U.V., Karde, V., Ghoroi, C., Heng, J.Y.Y., Influence of particle properties on powder bulk behaviour and processability. Int. J. Pharm. 518 (2017), 138–154, 10.1016/j.ijpharm.2016.12.045.
Peng, T., Lin, S., Niu, B., Wang, X., Huang, Y., Zhang, X., Li, G., Pan, X., Wu, C., Influence of physical properties of carrier on the performance of dry powder inhalers. Acta Pharm. Sinica B 6 (2016), 308–318, 10.1016/j.apsb.2016.03.011.
Kaialy, W., A review of factors affecting electrostatic charging of pharmaceuticals and adhesive mixtures for inhalation. Int. J. Pharm. 503 (2016), 262–276, 10.1016/j.ijpharm.2016.01.076.
Sarangi, S., Simonsson, A., Frenning, G., Segregation in inhalable powders: quantification of the effect of vibration on adhesive mixtures. Eur. J. Pharm. Biopharm. 187 (2023), 107–119, 10.1016/j.ejpb.2023.04.006.
Healy, A.M., Amaro, M.I., Paluch, K.J., Tajber, L., Dry powders for oral inhalation free of lactose carrier particles. Adv. Drug Deliv. Rev. 75 (2014), 32–52, 10.1016/j.addr.2014.04.005.
Kaialy, W., Alhalaweh, A., Velaga, S.P., Nokhodchi, A., Influence of lactose carrier particle size on the aerosol performance of budesonide from a dry powder inhaler. Powder Technol. 227 (2012), 74–85, 10.1016/j.powtec.2012.03.006.
Alhajj, 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. Powder Technol. 384 (2021), 313–331, 10.1016/j.powtec.2021.02.031.
Behara, S.R.B., Larson, I., Kippax, P., Morton, D.A.V., Stewart, P., The kinetics of cohesive powder de-agglomeration from three inhaler devices. Int. J. Pharm. 421 (2011), 72–81, 10.1016/j.ijpharm.2011.09.024.
Hoppentocht, M., Hagedoorn, P., Frijlink, H.W., de Boer, A.H., Technological and practical challenges of dry powder inhalers and formulations. Adv. Drug Deliv. Rev. 75 (2014), 18–31, 10.1016/j.addr.2014.04.004.
de Boer, A.H., Hagedoorn, P., Hoppentocht, M., Buttini, F., Grasmeijer, F., Frijlink, H.W., Dry powder inhalation: past, present and future. Expert Opin. Drug Deliv. 14 (2017), 499–512, 10.1080/17425247.2016.1224846.
Kadota, K., Tanaka, M., Nishiyama, H., Tse, J.Y., Uchiyama, H., Shirakawa, Y., Tozuka, Y., An effective approach to modify the inhalable betamethasone powders based on morphology and surface control using a biosurfactant. Powder Technol. 376 (2020), 517–526, 10.1016/j.powtec.2020.08.063.
Chow, A.H.L., Tong, H.H.Y., Chattopadhyay, P., Shekunov, B.Y., Particle engineering for pulmonary drug delivery. Pharm. Res. 24 (2007), 411–437, 10.1007/s11095-006-9174-3.
Chaurasiya, B., Zhao, Y.Y., Dry powder for pulmonary delivery: a comprehensive review. Pharmaceutics 13 (2021), 1–28, 10.3390/pharmaceutics13010031.
Baumann, J.M., Adam, M.S., Wood, J.D., Engineering advances in spray drying for pharmaceuticals. Annu. Rev. Chem. Biomol. Eng. 12 (2021), 217–240, 10.1146/annurev-chembioeng.
Cabral-Marques, H., Almeida, R., Optimisation of spray-drying process variables for dry powder inhalation (DPI) formulations of corticosteroid/cyclodextrin inclusion complexes. Eur. J. Pharm. Biopharm. 73 (2009), 121–129, 10.1016/j.ejpb.2009.05.002.
Scherließ, R., Bock, S., Bungert, N., Neustock, A., Valentin, L., Particle engineering in dry powders for inhalation. Eur. J. Pharm. Sci., 172, 2022, 10.1016/j.ejps.2022.106158.
El-Gendy, N., Bailey, M.M., Berkland, C., Particle engineering technologies for pulmonary drug delivery. Smyth, H.D.C., Hickey, A.J., (eds.) Controlled Pulmonary Drug Delivery, 2011, Advances in Delivery Science and Technology, Springer, Austin, 283–312, 10.1007/978-1-4419-9745-6.
Cui, Y., Zhang, X., Wang, W., Huang, Z., Zhao, Z., Wang, G., Cai, S., Jing, H., Huang, Y., Pan, X., Wu, C., Moisture-resistant co-spray-dried netilmicin with l-leucine as dry powder inhalation for the treatment of respiratory infections. Pharmaceutics, 10, 2018, 10.3390/pharmaceutics10040252.
Mangal, S., Gengenbach, T., Millington-Smith, D., Armstrong, B., Morton, D.A.V., Larson, I., Relationship between the cohesion of guest particles on the flow behaviour of interactive mixtures. Eur. J. Pharm. Biopharm. 102 (2016), 168–177, 10.1016/j.ejpb.2016.03.012.
Dufour, G., Bigazzi, W., Wong, N., Boschini, F., De Tullio, P., Piel, G., Cataldo, D., Evrard, B., Interest of cyclodextrins in spray-dried microparticles formulation for sustained pulmonary delivery of budesonide. Int. J. Pharm. 495 (2015), 869–878, 10.1016/j.ijpharm.2015.09.052.
Lechanteur, A., Plougonven, E., Orozco, L., Lumay, G., Vandewalle, N., Léonard, A., Evrard, B., Engineered-inhaled particles: influence of carbohydrates excipients nature on powder properties and behavior. Int. J. Pharm., 613, 2022, 10.1016/j.ijpharm.2021.121319.
Lechanteur, A., Gresse, E., Orozco, L., Plougonven, E., Léonard, A., Vandewalle, N., Lumay, G., Evrard, B., Inhalation powder development without carrier: how to engineer ultra-flying microparticles?. Eur. J. Pharm. Biopharm. 191 (2023), 26–35, 10.1016/j.ejpb.2023.08.010.
Shanmugam, S., Granulation techniques and technologies: recent progresses. BioImpacts 5 (2015), 55–63, 10.15171/bi.2015.04.
Etschmann, C., Scherließ, R., Formulation of rifampicin softpellets for high dose delivery to the lungs with a novel high dose dry powder inhaler. Int. J. Pharm., 617, 2022, 10.1016/j.ijpharm.2022.121606.
Saharan, V.A., Kataria, M.K., Kharb, V., Choudhury, P.K., Kukkar, V., Kataria, M., Choudhury, K., Ordered mixing: mechanism, process and applications. Asian J. Pharm. Sci. 3 (2008), 240–259.
Pinto, J.T., Stranzinger, S., Kruschitz, A., Faulhammer, E., Stegemann, S., Roblegg, E., Paudel, A., Insights into the processability and performance of adhesive blends of inhalable jet-milled and spray dried salbutamol sulphate at different drug loads. J. Drug Deliv. Sci. Technol. 48 (2018), 466–477, 10.1016/j.jddst.2018.10.014.
Ye, Y., Shi, T., Fan, Z., Bai, C., Ma, Y., Zhu, J., Elucidation of the using condition and working mechanism of tertiary lactose in dry powder formulations for inhalation. Powder Technol., 427, 2023, 10.1016/j.powtec.2023.118709.
Zellnitz, S., Lamešić, D., Stranzinger, S., Pinto, J.T., Planinšek, O., Paudel, A., Spherical agglomerates of lactose as potential carriers for inhalation. Eur. J. Pharm. Biopharm. 159 (2021), 11–20, 10.1016/j.ejpb.2020.12.015.
Shah, K.R., Badawy, S.I.F., Szemraj, M.M., Gray, D.B., Hussain, M.A., Assessment of segregation potential of powder blends. Pharm. Dev. Technol. 12 (2007), 457–462, 10.1080/10837450701556834.
Podczeck, F., The relationship between physical properties of lactose monohydrate and the aerodynamic behaviour of adhered drug particles. Int. J. Pharm. 160 (1998), 119–130, 10.1016/S0378-5173(97)00313-X.
Tan, B.M.J., Chan, L.W., Heng, P.W.S., Characterizing the surface roughness length scales of lactose carrier particles in dry powder inhalers. Mol. Pharm. 15 (2018), 1635–1642, 10.1021/acs.molpharmaceut.8b00007.
MEGGLE, Group Wasserburg, Technical Brochure InhaLac®; Dry Powder Inhalation, Sieved/Milled/Micronized Lactose. www.meggle-pharma.com, 2021.
Jadhav, H.T., Ozoh, C., Marripudi, S.T., Cao, X., Rosentrater, K.A., Studies on ground corn flowability as affected by particle size and moisture content. 2017 ASABE Annual International Meeting, American Society of Agricultural and Biological Engineers, 2017, 10.13031/aim.201701175.
Abiona, O., Wyatt, D., Koner, J., Mohammed, A., The optimisation of carrier selection in dry powder inhaler formulation and the role of surface energetics. Biomedicines, 10, 2022, 2707, 10.3390/biomedicines10112707.
Begat, P., Morton, D.A.V., Staniforth, J.N., Price, R., The cohesive-adhesive balances in dry powder inhaler formulations II: influence on fine particle delivery characteristics. Pharm. Res. 21 (2004), 1826–1833, 10.1023/B:PHAM.0000045236.60029.cb.
Nguyen, D., Rasmuson, A., Björn, I.N., Thalberg, K., Mechanistic time scales in adhesive mixing investigated by dry particle sizing. Eur. J. Pharm. Sc. 69 (2015), 19–25, 10.1016/j.ejps.2014.12.016.
Karner, S., Urbanetz, N.A., Triboelectric characteristics of mannitol based formulations for the application in dry powder inhalers. Powder Technol. 235 (2013), 349–358, 10.1016/j.powtec.2012.10.034.
Huber, G., Wirth, K.E., Electrostatically supported surface coating of solid particles in liquid nitrogen for use in dry-powder-inhalers. Powder Technol. 134 (2003), 181–192, 10.1016/S0032-5910(03)00128-1.
Persson, G., Olsson, B., Soliman, S., The impact of inspiratory effort on inspiratory flow through Turbuhaler® in asthmatic patients. Eur. Resp. J. 10 (1997), 681–684, 10.1183/09031936.97.10030681.
Farkas, Á., Horváth, A., Tomisa, G., Kovács, T., Böcskei, R.M., Kis, E., Varga, J., Do we really target the receptors? Deposition and co-deposition of ICS-LABA fixed combination drugs. Eur. J. Pharm. Sci., 174, 2022, 10.1016/j.ejps.2022.106186.
Israel, S., Kumar, A., DeAngelis, K., Aurivillius, M., Dorinsky, P., Roche, N., Usmani, O.S., Pulmonary deposition of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler formulated using co-suspension delivery technology in healthy male subjects. Eur. J. Pharm. Sci., 153, 2020, 10.1016/j.ejps.2020.105472.
Heo, Y.A., Budesonide/Glycopyrronium/formoterol: a review in COPD. Drugs 81 (2021), 1411–1422, 10.1007/s40265-021-01562-6.
Azouz, W., Chetcuti, P., Hosker, H.S.R., Saralaya, D., Stephenson, J., Chrystyn, H., The inhalation characteristics of patients when they use different dry powder inhalers. J. Aerosol Med. Pulm. Drug Deliv. 28 (2015), 35–42, 10.1089/jamp.2013.1119.
Voss, A., Finlay, W.H., Deagglomeration of dry powder pharmaceutical aerosols. Int. J. Pharm. 248 (2002), 39–50, 10.1016/s0378-5173(02)00319-8.
Groß, R., Berkenfeld, K., Schulte, C., Ebert, A., Sule, S., Sule, A., Lamprecht, A., State of the art in capsule-based dry powder inhalers: Deagglomeration techniques and the consequences for formulation Aerosolization. Pharmaceutics, 14, 2022, 10.3390/pharmaceutics14061185.
Begat, P., Price, R., Harris, H., Staniforth, J., The influence of force control agents on the cohesive-adhesive balance in dry powder inhaler formulations. KONA Powder and Particle J. 23 (2005), 109–121, 10.14356/kona.2005014.
Jüptner, A., Scherließ, R., Spray dried formulations for inhalation—meaningful characterisation of powder properties. Pharmaceutics, 12, 2020, 10.3390/pharmaceutics12010014.
Sibum, I., Hagedoorn, P., Botterman, C.O., Frijlink, H.W., Grasmeijer, F., Automated filling equipment allows increase in the maximum dose to be filled in the cyclops® high dose dry powder inhalation device while maintaining dispersibility. Pharmaceutics 12 (2020), 1–14, 10.3390/pharmaceutics12070645.
Faria-Urbina, M., Ung, K.T., Lawler, L., Zisman, L.S., Waxman, A.B., Inspiratory flow patterns with dry powder inhalers of low and medium flow resistance in patients with pulmonary arterial hypertension. Pulm. Circ., 11, 2021, 10.1177/20458940211012591.
Abadelah, M., Al-Assadi, J., Rooney, J., Larhrib, H., The effect of inspiratory parameters after two separate inhalations on the dose emission of theophylline from low and high resistance dry powder inhalers. Saudi Pharm. J. 28 (2020), 74–86, 10.1016/j.jsps.2019.11.007.
Haughney, J., Lee, A.J., McKnight, E., Pertsovskaya, I., O'Driscoll, M., Usmani, O.S., Peak inspiratory flow measured at different inhaler resistances in patients with asthma. J. Allergy Clin. Immun Pract. 9 (2021), 890–896, 10.1016/j.jaip.2020.09.026.
Buttini, F., Brambilla, G., Copelli, D., Sisti, V., Balducci, A.G., Bettini, R., Pasquali, I., Effect of flow rate on in vitro aerodynamic performance of NEXThaler® in comparison with Diskus® and Turbohaler® dry powder inhalers. J. Aerosol Med. Pulm. Drug Deliv. 29 (2016), 167–178, 10.1089/jamp.2015.1220.