Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder
Tushar Saha, Shubhra Sinha, Rhodri Harfoot, Miguel E Quiñones-Mateu, Shyamal C Das
Pharmaceutics, doi:10.3390/pharmaceutics14071432
SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit at relatively high concentrations, which is difficult to achieve in the lung. In this study, we tested the spray-drying conditions to develop an inhalable dry powder formulation that could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a proof-of-concept, we evaluated spray-drying conditions that could lead to the development of antivirals in an inhalable dry powder formulation, which could then be used to ensure sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle experiments to evaluate our system, including physical characterization and in vitro aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini spray-dryer (Buchi B-290), using a 2 3 factorial design and manipulating spray-drying conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 • C and 100 • C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the size range of 1-5 µm and amorphous in nature with wrinkle morphology. We observed a higher fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet temperature (100 • C) and the presence of L-leucine (10% w/w). The stability study conducted for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 • C/<15% RH and 25 ± 2 • C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 replication in vitro with a potency similar to ivermectin solution (EC 50 values of 15.8 µM and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In summary, we were able to manipulate the spray-drying conditions to develop an effective ivermectin inhalable dry powder. Ongoing studies based on this system will allow the development of novel formulations based on single or combinations of drugs that could be used to inhibit SARS-CoV-2 replication in the respiratory tract.
Conflicts of Interest: The authors declare no conflict of interest.
References
Ahmed, Karim, Ross, Hossain, Clemens et al., A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness, Int. J. Infect. Dis,
doi:10.1016/j.ijid.2020.11.191Ari, Practical strategies for a safe and effective delivery of aerosolized medications to patients with COVID-19, Respir. Med,
doi:10.1016/j.rmed.2020.105987Benke, Farkas, Szabó-Révész, Ambrus, Development of an Innovative, Carrier-Based Dry Powder Inhalation Formulation Containing Spray-Dried Meloxicam Potassium to Improve the In Vitro and In Silico Aerodynamic Properties, Pharmaceutics,
doi:10.3390/pharmaceutics12060535Bp, British Pharmacopoeia; Stationery Office: London, UK
Brunaugh, Seo, Warnken, Ding, Seo et al., Development and evaluation of inhalable composite niclosamide-lysozyme particles: A broad-spectrum, patient-adaptable treatment for coronavirus infections and sequalae, PLoS ONE,
doi:10.1371/journal.pone.0246803Carter, Rowley, Fletcher, Stylianopoulos, Measurement of Electrostatic Charge Decay in Pharmaceutical Powders and Polymer Materials Used in Dry Powder Inhaler Device, Drug Dev. Ind. Pharm,
doi:10.3109/03639049809089953Chable-Bessia, Boullé, Neyret, Swain, Hénaut et al., Low Selectivity Indices of Ivermectin and Macrocyclic Lactones on SARS-CoV-2 Replication In Vitro, Covid
Chaccour, Abizanda, Irigoyen-Barrio, Casellas, Aldaz et al., Nebulized ivermectin for COVID-19 and other respiratory diseases, a proof of concept, dose-ranging study in rats, Sci. Rep
Chaccour, Hammann, Rabinovich, Ivermectin to reduce malaria transmission I. Pharmacokinetic and pharmacodynamic considerations regarding efficacy and safety, Malar. J,
doi:10.1186/s12936-017-1801-4Charmet, Schaeffer, Grant, Galmiche, Cheny et al., Impact of original, B.1.1.7, and B.1.351/P.1 SARS-CoV-2 lineages on vaccine effectiveness of two doses of COVID-19 mRNA vaccines: Results from a nationwide case-control study in France,
doi:10.1016/j.lanepe.2021.100171Chen, Fei, Chen, Sargsyan, Chang et al., Synergistic Inhibition of SARS-CoV-2 Replication Using Disulfiram/Ebselen and Remdesivir, ACS Pharmacol. Transl. Sci,
doi:10.1021/acsptsci.1c00022Chew, Shekunov, Tong, Chow, Savage et al., Effect of amino acids on the dispersion of disodium cromoglycate powders, J. Pharm. Sci,
doi:10.1002/jps.20426Costela-Ruiz, Illescas-Montes, Puerta-Puerta, Ruiz, Melguizo-Rodriguez, SARS-CoV-2 infection: The role of cytokines in COVID-19 disease, Cytokine Growth Factor Rev,
doi:10.1016/j.cytogfr.2020.06.001Delandre, Gendrot, Jardot, Le Bideau, Boxberger et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals,
doi:10.3390/ph15040445Dhama, Sharun, Tiwari, Dadar, Malik et al., COVID-19, an emerging coronavirus infection: Advances and prospects in designing and developing vaccines, immunotherapeutics, and therapeutics, Hum. Vaccin. Immunother,
doi:10.1080/21645515.2020.1735227Dong, Song, Lian, Fu, Gong, Subcutaneously injected ivermectin-loaded mixed micelles: Formulation, pharmacokinetics and local irritation study, Drug Dev,
doi:10.3109/10717544.2014.956849Eedara, Alabsi, Encinas-Basurto, Polt, Ledford et al., Inhalation Delivery for the Treatment and Prevention of COVID-19 Infection, Pharmaceutics,
doi:10.3390/pharmaceutics13071077Eedara, Tucker, Das, In vitro dissolution testing of respirable size anti-tubercular drug particles using a small volume dissolution apparatus, Int. J. Pharm,
doi:10.1016/j.ijpharm.2019.01.035Eedara, Tucker, Zujovic, Rades, Price et al., Crystalline adduct of moxifloxacin with trans-cinnamic acid to reduce the aqueous solubility and dissolution rate for improved residence time in the lungs, Eur. J. Pharm. Sci,
doi:10.1016/j.ejps.2019.104961Elalfy, Besheer, El-Mesery, El-Gilany, Soliman et al., Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19, J. Med. Virol,
doi:10.1002/jmv.26880Emary, Golubchik, Aley, Ariani, Angus et al., Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): An exploratory analysis of a randomised controlled trial, Lancet,
doi:10.1016/S0140-6736(21)00628-0Ferdynand, Nokhodchi, Co-spraying of carriers (mannitol-lactose) as a method to improve aerosolization performance of salbutamol sulfate dry powder inhaler, Drug Deliv. Transl. Res,
doi:10.1007/s13346-020-00707-6Ghasemian, Vatanara, Rouini, Rouholamini Najafabadi, Gilani et al., Inhaled sildenafil nanocomposites: Lung accumulation and pulmonary pharmacokinetics, Pharm. Dev. Technol,
doi:10.3109/10837450.2015.1086369Harfoot, Lawley, Hernandez, Kuang, Grant et al., Characterization of the First SARS-CoV-2 Isolates from Aotearoa New Zealand as Part of a Rapid Response to the COVID-19 Pandemic,
doi:10.3390/v14020366Hassoun, Ho, Muddle, Buttini, Parry et al., Formulating powder-device combinations for salmeterol xinafoate dry powder inhalers, Int. J. Pharm,
doi:10.1016/j.ijpharm.2015.05.028Hassoun, Malmlof, Scheibelhofer, Kumar, Bansal et al., Use of PBPK Modeling To Evaluate the Performance of DissolvIt, a Biorelevant Dissolution Assay for Orally Inhaled Drug Products, Mol. Pharm,
doi:10.1021/acs.molpharmaceut.8b01200Heidary, Gharebaghi, Ivermectin: A systematic review from antiviral effects to COVID-19 complementary regimen, J. Antibiot,
doi:10.1038/s41429-020-0336-zHeimfarth, Serafini, Martins-Filho, Quintans, Quintans-Junior, Drug repurposing and cytokine management in response to COVID-19: A review, Int. Immunopharmacol,
doi:10.1016/j.intimp.2020.106947Heyder, Gebhart, Rudolf, Schiller, Stahlhofen, Deposition of particles in the human respiratory tract in the size range 0.005-15 µm, J. Aerosol. Sci,
doi:10.1016/0021-8502(86)90035-2Hickey, Da Rocha, Pharmaceutical Inhalation Aerosol Technology
Hoppentocht, Hagedoorn, Frijlink, De Boer, Technological and practical challenges of dry powder inhalers and formulations, Adv. Drug Deliv. Rev,
doi:10.1016/j.addr.2014.04.004Kissler, Tedijanto, Goldstein, Grad, Lipsitch, Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period, Science,
doi:10.1126/science.abb5793Kumar, Ter Ellen, Bouma, Troost, Van De Pol et al., Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells, Antimicrob. Agents Chemother,
doi:10.1128/AAC.01543-21Letko, Marzi, Munster, Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses, Nat. Microbiol,
doi:10.1038/s41564-020-0688-yLi, Moore, Vasilieva, Sui, Wong et al., Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus, Nature,
doi:10.1038/nature02145Li, Sun, Parumasivam, Denman, Gengenbach et al., L-Leucine as an excipient against moisture on in vitro aerosolization performances of highly hygroscopic spray-dried powders, Eur. J. Pharm. Biopharm,
doi:10.1016/j.ejpb.2016.02.010Lim, Hor, Tay, Mat, Jelani et al., Efficacy of Ivermectin Treatment on Disease Progression Among Adults with Mild to Moderate COVID-19 and Comorbidities: The I-TECH Randomized Clinical Trial, JAMA Intern. Med,
doi:10.1001/jamainternmed.2022.0189Lopez-Medina, Lopez, Hurtado, Davalos, Ramirez et al., Effect of Ivermectin on Time to Resolution of Symptoms among Adults with Mild COVID-19: A Randomized Clinical Trial, JAMA,
doi:10.1001/jama.2021.3071Mangal, Nie, Xu, Guo, Cavallaro et al., Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation, Pharm. Res,
doi:10.1007/s11095-017-2334-9Mansour, Shamma, Ahmed, Sabry, Esmat et al., Safety of inhaled ivermectin as a repurposed direct drug for treatment of COVID-19: A preclinical tolerance study, Int. Immunopharmacol
Mehta, Dry Powder Inhalers: A Focus on Advancements in Novel Drug Delivery Systems, J. Drug Deliv,
doi:10.1155/2016/8290963Momin, Adhikari, Sinha, Larson, Das, Roflumilast Powders for Chronic Obstructive Pulmonary Disease: Formulation Design and the Influence of Device, Inhalation Flow Rate, and Storage Relative Humidity on Aerosolization, Pharmaceutics,
doi:10.3390/pharmaceutics13081254Momin, Sinha, Tucker, Doyle, Das, Dry powder formulation of kanamycin with enhanced aerosolization efficiency for drug-resistant tuberculosis, Int. J. Pharm,
doi:10.1016/j.ijpharm.2017.06.004Nasreen, Chung, He, Brown, Gubbay et al., Effectiveness of COVID-19 vaccines against symptomatic SARS-CoV-2 infection and severe outcomes with variants of concern in Ontario, Nat. Microbiol,
doi:10.1038/s41564-021-01053-0Patel, Patel, Chakraborty, Shukla, Revealing facts behind spray dried solid dispersion technology used for solubility enhancement, Saudi Pharm. J,
doi:10.1016/j.jsps.2013.12.013Peña-Silva, Duffull, Steer, Jaramillo-Rincon, Gwee et al., Pharmacokinetic considerations on the repurposing of ivermectin for treatment of COVID-19, Br. J. Clin. Pharmacol,
doi:10.1111/bcp.14476Pignatello, Leonardi, Fuochi, Petronio Petronio, Greco et al., A Method for Efficient Loading of Ciprofloxacin Hydrochloride in Cationic Solid Lipid Nanoparticles: Formulation and Microbiological Evaluation, Nanomaterials,
doi:10.3390/nano8050304Rabi, Al Zoubi, Kasasbeh, Salameh, Al-Nasser, SARS-CoV-2 and Coronavirus Disease, What We Know So Far. Pathogens,
doi:10.3390/pathogens9030231Reis, Silva, Silva, Thabane, Milagres et al., Effect of Early Treatment with Ivermectin among Patients with COVID-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2115869Rolim, Santos, Chaves, Gonçalves, Freitas-Neto et al., Preformulation study of ivermectin raw material, J. Therm. Anal. Calorim,
doi:10.1007/s10973-014-3691-9Schmith, Zhou, Lohmer, The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19, Clin. Pharmacol. Ther,
doi:10.1002/cpt.1889Seville, Learoyd, Li, Williamson, Birchall, Amino acid-modified spray-dried powders with enhanced aerosolisation properties for pulmonary drug delivery, Powder Technol,
doi:10.1016/j.powtec.2007.03.046Simon, Amaro, Cabral, Healy, De Sousa, Development of a novel dry powder inhalation formulation for the delivery of rivastigmine hydrogen tartrate, Int. J. Pharm,
doi:10.1016/j.ijpharm.2016.01.066Sohrabi, Alsafi, O'neill, Khan, Kerwan et al., World Health Organization declares global emergency: A review of the 2019 novel coronavirus (COVID-19), Int. J. Surg,
doi:10.1016/j.ijsu.2020.02.034Son, Worth Longest, Hindle, Aerosolization characteristics of dry powder inhaler formulations for the excipient enhanced growth (EEG) application: Effect of spray drying process conditions on aerosol performance, Int. J. Pharm,
doi:10.1016/j.ijpharm.2013.01.003Sou, Kaminskas, Nguyen, Carlberg, Mcintosh et al., The effect of amino acid excipients on morphology and solid-state properties of multi-component spray-dried formulations for pulmonary delivery of biomacromolecules, Eur. J. Pharm. Biopharm,
doi:10.1016/j.ejpb.2012.10.015Thomas, Moreira, Kitchin, Absalon, Gurtman et al., Safety and Efficacy of the BNT162b2 mRNA COVID-19 Vaccine through 6 months, N. Engl. J. Med,
doi:10.1056/NEJMoa2110345Walls, Park, Tortorici, Wall, Mcguire et al., Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein,
doi:10.1016/j.cell.2020.02.058Williams, Adams, Poochikian, Hauck, Content uniformity and dose uniformity: Current approaches, statistical analyses, and presentation of an alternative approach, with special reference to oral inhalation and nasal drug products, Pharm. Res,
doi:10.1023/A:1015114821387Yang, Yang, Ren, Mei, Effects of formulation and operating variables on zanamivir dry powder inhalation characteristics and aerosolization performance, Drug Deliv,
doi:10.3109/10717544.2014.883113Young, Sung, Traini, Kwok, Chiou et al., Influence of humidity on the electrostatic charge and aerosol performance of dry powder inhaler carrier based systems, Pharm. Res,
doi:10.1007/s11095-006-9218-8Zhu, Tan, Ng, Shen, Zhou et al., Analysis of the influence of relative humidity on the moisture sorption of particles and the aerosolization process in a dry powder inhaler, J. Aerosol. Sci,
doi:10.1016/j.jaerosci.2008.02.003Zijlstra, Hinrichs, De Boer, Frijlink, The role of particle engineering in relation to formulation and deagglomeration principle in the development of a dry powder formulation for inhalation of cetrorelix, Eur. J. Pharm. Sci,
doi:10.1016/j.ejps.2004.06.005{ 'indexed': {'date-parts': [[2023, 8, 29]], 'date-time': '2023-08-29T13:21:54Z', 'timestamp': 1693315314967},
'reference-count': 73,
'publisher': 'MDPI AG',
'issue': '7',
'license': [ { 'start': { 'date-parts': [[2022, 7, 8]],
'date-time': '2022-07-08T00:00:00Z',
'timestamp': 1657238400000},
'content-version': 'vor',
'delay-in-days': 0,
'URL': 'https://creativecommons.org/licenses/by/4.0/'}],
'funder': [{'name': 'Laurenson Bequest Award', 'award': ['LA394', 'Nil']}],
'content-domain': {'domain': [], 'crossmark-restriction': False},
'abstract': '<jats:p>SARS-CoV-2, the causative agent of COVID-19, predominantly affects the respiratory '
'tract. As a consequence, it seems intuitive to develop antiviral agents capable of targeting '
'the virus right on its main anatomical site of replication. Ivermectin, a U.S. FDA-approved '
'anti-parasitic drug, was originally shown to inhibit SARS-CoV-2 replication in vitro, albeit '
'at relatively high concentrations, which is difficult to achieve in the lung. In this study, '
'we tested the spray-drying conditions to develop an inhalable dry powder formulation that '
'could ensure sufficient antiviral drug concentrations, which are difficult to achieve in the '
'lungs based on the oral dosage used in clinical trials. Here, by using ivermectin as a '
'proof-of-concept, we evaluated spray-drying conditions that could lead to the development of '
'antivirals in an inhalable dry powder formulation, which could then be used to ensure '
'sufficient drug concentrations in the lung. Thus, we used ivermectin in proof-of-principle '
'experiments to evaluate our system, including physical characterization and in vitro '
'aerosolization of prepared dry powder. The ivermectin dry powder was prepared with a mini '
'spray-dryer (Buchi B-290), using a 23 factorial design and manipulating spray-drying '
'conditions such as feed concentration (0.2% w/v and 0.8% w/v), inlet temperature (80 °C and '
'100 °C) and presence/absence of L-leucine (0% and 10%). The prepared dry powder was in the '
'size range of 1–5 μm and amorphous in nature with wrinkle morphology. We observed a higher '
'fine particle fraction (82.5 ± 1.4%) in high feed concentration (0.8% w/v), high inlet '
'temperature (100 °C) and the presence of L-leucine (10% w/w). The stability study conducted '
'for 28 days confirmed that the spray-dried powder was stable at 25 ± 2 °C/<15% RH and 25 ± '
'2 °C/ 53% RH. Interestingly, the ivermectin dry powder formulation inhibited SARS-CoV-2 '
'replication in vitro with a potency similar to ivermectin solution (EC50 values of 15.8 µM '
'and 14.1 µM, respectively), with a comparable cell toxicity profile in Calu-3 cells. In '
'summary, we were able to manipulate the spray-drying conditions to develop an effective '
'ivermectin inhalable dry powder. Ongoing studies based on this system will allow the '
'development of novel formulations based on single or combinations of drugs that could be used '
'to inhibit SARS-CoV-2 replication in the respiratory tract.</jats:p>',
'DOI': '10.3390/pharmaceutics14071432',
'type': 'journal-article',
'created': {'date-parts': [[2022, 7, 11]], 'date-time': '2022-07-11T04:06:21Z', 'timestamp': 1657512381000},
'page': '1432',
'source': 'Crossref',
'is-referenced-by-count': 5,
'title': 'Manipulation of Spray-Drying Conditions to Develop an Inhalable Ivermectin Dry Powder',
'prefix': '10.3390',
'volume': '14',
'author': [ {'given': 'Tushar', 'family': 'Saha', 'sequence': 'first', 'affiliation': []},
{'given': 'Shubhra', 'family': 'Sinha', 'sequence': 'additional', 'affiliation': []},
{'given': 'Rhodri', 'family': 'Harfoot', 'sequence': 'additional', 'affiliation': []},
{ 'ORCID': 'http://orcid.org/0000-0001-9170-5601',
'authenticated-orcid': False,
'given': 'Miguel E.',
'family': 'Quiñones-Mateu',
'sequence': 'additional',
'affiliation': []},
{'given': 'Shyamal C.', 'family': 'Das', 'sequence': 'additional', 'affiliation': []}],
'member': '1968',
'published-online': {'date-parts': [[2022, 7, 8]]},
'reference': [ { 'key': 'ref1',
'unstructured': 'World Health Organization Coronavirus Disease (COVID-19) Pandemic\n'
'https://www.who.int/emergencies/diseases/novel-coronavirus-2019'},
{'key': 'ref2', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/acsptsci.1c00022'},
{'key': 'ref3', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0140-6736(21)00628-0'},
{'key': 'ref4', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2110345'},
{'key': 'ref5', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41564-021-01053-0'},
{'key': 'ref6', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.lanepe.2021.100171'},
{'key': 'ref7', 'doi-asserted-by': 'publisher', 'DOI': '10.1126/science.abb5793'},
{'key': 'ref8', 'doi-asserted-by': 'publisher', 'DOI': '10.1080/21645515.2020.1735227'},
{'key': 'ref9', 'doi-asserted-by': 'publisher', 'DOI': '10.1136/bmj.m810'},
{'key': 'ref10', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pathogens9030231'},
{'key': 'ref11', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/nature02145'},
{'key': 'ref12', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cytogfr.2020.06.001'},
{'key': 'ref13', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41564-020-0688-y'},
{'key': 'ref14', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jaut.2020.102433'},
{'key': 'ref15', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijsu.2020.02.034'},
{'key': 'ref16', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.bbrc.2020.02.071'},
{'key': 'ref17', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.cell.2020.02.058'},
{'key': 'ref18', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41429-020-0336-z'},
{'key': 'ref19', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.antiviral.2020.104787'},
{'key': 'ref20', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijid.2020.11.191'},
{'key': 'ref21', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.intimp.2020.106947'},
{'key': 'ref22', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jama.2021.3071'},
{'key': 'ref23', 'doi-asserted-by': 'publisher', 'DOI': '10.1056/NEJMoa2115869'},
{'key': 'ref24', 'doi-asserted-by': 'publisher', 'DOI': '10.1001/jamainternmed.2022.0189'},
{'key': 'ref25', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/cpt.1889'},
{'key': 'ref26', 'doi-asserted-by': 'publisher', 'DOI': '10.1111/bcp.14476'},
{'key': 'ref27', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pharmaceutics13071077'},
{'key': 'ref28', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.intimp.2021.108004'},
{'key': 'ref29', 'doi-asserted-by': 'publisher', 'DOI': '10.1038/s41598-020-74084-y'},
{'key': 'ref30', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.rmed.2020.105987'},
{'key': 'ref31', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/S0962-8479(96)90069-6'},
{'key': 'ref32', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijpharm.2018.08.061'},
{'key': 'ref33', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s40248-015-0012-5'},
{'key': 'ref34', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijpharm.2015.05.028'},
{'key': 'ref35', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/0021-8502(86)90035-2'},
{'key': 'ref36', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pharmaceutics13081254'},
{'key': 'ref37', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ejps.2019.104961'},
{'key': 'ref38', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijpharm.2019.01.035'},
{'key': 'ref39', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/v14020366'},
{'key': 'ref40', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jsps.2013.12.013'},
{'key': 'ref41', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jps.20426'},
{'key': 'ref42', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ejpb.2012.10.015'},
{'key': 'ref43', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.powtec.2007.03.046'},
{'key': 'ref44', 'doi-asserted-by': 'publisher', 'DOI': '10.1371/journal.pone.0246803'},
{'key': 'ref45', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.powtec.2014.06.058'},
{'key': 'ref46', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ejpb.2016.02.010'},
{'key': 'ref47', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s10973-014-3691-9'},
{'key': 'ref48', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/nano8050304'},
{'key': 'ref49', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pharmaceutics13010031'},
{'key': 'ref50', 'doi-asserted-by': 'publisher', 'DOI': '10.3109/10717544.2014.883113'},
{'key': 'ref51', 'series-title': 'British Pharmacopoeia', 'author': 'BP', 'year': '2015'},
{'key': 'ref52', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijpharm.2017.06.004'},
{'key': 'ref53', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/pharmaceutics12060535'},
{'key': 'ref54', 'doi-asserted-by': 'publisher', 'DOI': '10.1023/A:1015114821387'},
{ 'key': 'ref55',
'series-title': 'Pharmaceutical Inhalation Aerosol Technology',
'author': 'Hickey',
'year': '2019'},
{'key': 'ref56', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.jaerosci.2008.02.003'},
{'key': 'ref57', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ejps.2004.06.005'},
{'key': 'ref58', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijpharm.2016.01.066'},
{'key': 'ref59', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s11095-017-2334-9'},
{'key': 'ref60', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.ijpharm.2013.01.003'},
{'key': 'ref61', 'doi-asserted-by': 'publisher', 'DOI': '10.1016/j.addr.2014.04.004'},
{'key': 'ref62', 'doi-asserted-by': 'publisher', 'DOI': '10.1155/2016/8290963'},
{'key': 'ref63', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s13346-020-00707-6'},
{'key': 'ref64', 'doi-asserted-by': 'publisher', 'DOI': '10.3109/10837450.2015.1086369'},
{'key': 'ref65', 'doi-asserted-by': 'publisher', 'DOI': '10.1007/s11095-006-9218-8'},
{'key': 'ref66', 'doi-asserted-by': 'publisher', 'DOI': '10.3109/03639049809089953'},
{'key': 'ref67', 'doi-asserted-by': 'publisher', 'DOI': '10.3109/10717544.2014.956849'},
{'key': 'ref68', 'doi-asserted-by': 'publisher', 'DOI': '10.1186/s12936-017-1801-4'},
{'key': 'ref69', 'doi-asserted-by': 'publisher', 'DOI': '10.1021/acs.molpharmaceut.8b01200'},
{'key': 'ref70', 'doi-asserted-by': 'publisher', 'DOI': '10.1002/jmv.26880'},
{'key': 'ref71', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/covid2010005'},
{'key': 'ref72', 'doi-asserted-by': 'publisher', 'DOI': '10.3390/ph15040445'},
{'key': 'ref73', 'doi-asserted-by': 'publisher', 'DOI': '10.1128/AAC.01543-21'}],
'container-title': 'Pharmaceutics',
'original-title': [],
'language': 'en',
'link': [ { 'URL': 'https://www.mdpi.com/1999-4923/14/7/1432/pdf',
'content-type': 'unspecified',
'content-version': 'vor',
'intended-application': 'similarity-checking'}],
'deposited': { 'date-parts': [[2022, 7, 11]],
'date-time': '2022-07-11T04:29:51Z',
'timestamp': 1657513791000},
'score': 1,
'resource': {'primary': {'URL': 'https://www.mdpi.com/1999-4923/14/7/1432'}},
'subtitle': [],
'short-title': [],
'issued': {'date-parts': [[2022, 7, 8]]},
'references-count': 73,
'journal-issue': {'issue': '7', 'published-online': {'date-parts': [[2022, 7]]}},
'alternative-id': ['pharmaceutics14071432'],
'URL': 'http://dx.doi.org/10.3390/pharmaceutics14071432',
'relation': {},
'ISSN': ['1999-4923'],
'subject': ['Pharmaceutical Science'],
'container-title-short': 'Pharmaceutics',
'published': {'date-parts': [[2022, 7, 8]]}}
