Engineering Inhalable Therapeutic Particles: Conventional and Emerging Approaches
Abstract
:1. Introduction
2. Physicochemical Properties of Inhaled Therapeutic Ingredients
2.1. Particle Size and Distribution
2.2. Particle Morphology
2.3. Crystallinity
2.4. Hygroscopicity
2.5. Surface Charge
3. Carriers and Excipients Used for Inhaled Dry Powder Formulations
4. Approaches for Particle Engineering
4.1. Top-Down Approaches
4.1.1. Ball Milling
4.1.2. Media Milling
4.1.3. Jet Milling
4.1.4. High Pressure Homogenization (HPH)
4.2. Bottom-Up Approaches
4.2.1. Spray Drying (SD)
Nanospray Drying
4.2.2. Freeze Drying (FD)/Lyophilization
4.2.3. Spray Freeze Drying (SFD)
4.2.4. Supercritical Fluid Technology (SCF)
4.2.5. Electrohydrodynamic Approaches
4.3. Hybrid Techniques
5. Other Emerging Approaches in Inhaled Therapeutic Ingredient Preparation
6. Clinical Trials for the Assessment of Inhaled Dry Powder Formulations
7. Prospects of Dry Powder Formulations for Inhalation
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Technique | Therapeutic Ingredient/API | Additives | Particle Properties | References |
---|---|---|---|---|
Top-down approaches | ||||
Jet milling and in situ micronization | Beclomethasone dipropionate | NA | ~5 µm, FPF 40% | [30] |
Micronization | Levodopa | L-Leucine | <5 µm Co-microionization with 2% leucine | [31] |
Jet milling | Diclofenac | NA | 2.36 µm, hollow crystal with different deposition patterns in NGI, jet-milled DF shows the best aerodynamic performance | [32] |
Dry jet milling | Simvastatin | NA | 2.2 µm, in vitro study with 60 L/min at MLI stage 3 filters with aerodynamic diameter < 6.8 µm | [33] |
HPH | Itraconazole | Mannitol and sodium taurocholate | 5.91 µm, with FPF 46.2 to 63.2% and increased solubility to 96 ng/mL | [34] |
Combined wet milling with aerosol flow reactor | Indomethacin | Mannitol and L-leucine | 0.96 µm | [35] |
Single-step co-jet milling | Ciprofloxacin HCl and Colistin sulfate | NA | <5.4 µm, FPF 57.5 and 80.2% therapeutic ingredients, respectively | [36] |
Bottom-up approaches | ||||
SD | N-acetylcysteine | Soya phosphatidylcholine, Cholesterol, Polysorbate 80 | 7 µm MMAD, yield 71%, respirable fraction 30% | [37] |
Rifampicin | Soya phosphatidylcholine, Cholesterol, Hydrogenated soybean phosphatidylcholine | ~2 µm, 70% loading of therapeutic ingredient, FPF 50% | [38] | |
Rifapentine | NA | 1.92 µm, FPF 83% | [39] | |
Isoniazide | L-α-soybean phosphatidylcholine, Cholesterol, Mannitol | 4.92 µm, FPF 15–35% with encapsulation of therapeutic ingredient 18–30% | [40] | |
Freeze-thaw followed by SD | Ciprofloxacine | Magnesium stearate and isoleucine | ~1 µm, FPF 66–70%, encapsulation efficiency 79% | [41] |
Co-SD | Docetaxel | Phosphatidylcholine, Cholesterol, Mannitol, Leucine | 3.1 µm | [42] |
Moxifloxacin | Phosphatidylcholine, Cholesterol, Dextran | <5 µm, FPF 75% with deep lung deposition in rats | [43] | |
Oseltamivir phosphate | Ovelecithin, Cholesterol, Leucine | ~3.5 µm, FPF 35%, deposition studies show therapeutic ingredient release by twin-stage impinger | [44] | |
Salmon calcitonin | Sodium tripolyphosphate, Chitosan, Mannitol | 2.5–4.7 μm, FPF 63.5% with ACI | [45] | |
Azethromycin | Not mentioned | 1.6 µm | [46] | |
Paclitaxel | Dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol | 2.3 µm, powder deposition in all stages of NGI, with a higher dose at the lower stages | [47] | |
Tobramycin | Poly(lactic-co-glycolic acid), Poly(vinyl alcohol) | 3.3 µm | [48] | |
Tobramycin (PulmoSphere™) | Distearoylphosphatidlcholin, perflurooctyl bromide | ~5 µm | [49] | |
Zanamivir (Relenza® Glaxo) | Mannitol, L-leucine, Poloxamer 188 | 2.3 µm, in vitro deposition of 58%, and 116% bioavailability relative to Relenza® | [50] | |
Meloxicam | L-leucin, ammonium bicarbonate, sodium hyaluronate | In carrier-free formulations with 2.5 µm, the fine particle fraction and emitted fraction were higher for large porous particles than in non-porous formulations | [51] | |
Dexamethasone palmitate (Pro-therapeutic ingredient of dexamethasone) | 1,2-Dipalmitoyl-sn- Glycero-3- Phosphocholine (DPPC) and Hyaluronic Acid (HA) | Around 13 μm MMAD with a tap density of 0.05 g/cm3 and FPF of 40%. Large porous particles show sustained release, and the MMAD varies with therapeutic ingredient concentration. | [52] | |
SFD | Theophylline anhydrate and oxalic acid | NA | 3.0 µm Geometric mean diameter of 7.20 µm | [53] |
Levofloxacin | Polycaprolactone, L-leucine, Mannitol | ~4–5 µm | [54] | |
Levofloxacin | Soybean lecithin, D-mannitol, L-leucine | 5.6 µm | [54] | |
Small interfering RNA | Mannitol | 10–14.9 µm, an aerosol performance study using NGI showed an emitted fraction (EF) and FPF of 91% and 28%, respectively | [55] | |
Voriconazole | Mannitol | 3.8 µm, FPF 40% in NGI | [56] | |
Octreotide acetate | Mannitol, ammonium carbonate | 2.6 µm, FPF 40%, 88% bioavailability relative to commercial products | [57] | |
Human IgG | Hydroxypropyl β-cyclodextrin, trehalose | ~5.32 µm, FPF 51.29%, and particle behavior studied by the Anderson cascade impactor | [58] | |
PlasmidDNA-Luc | Β-benzyl-L-aspartate N-carboxy-anhydride | 7.6 µm, FPF 54%, in vitro inhalation study performed on ACI deposited in stage 3 and lower parts | [59] | |
SCF | Fluticasone-17-propionte | Poloxamer 188 | ~1.69 µm, FPF 61.9%, aerosol performance studied by NGI | [60] |
Salmon calcitonin | Inulin, Trehalose, Chitosan, Sodium taurocholate, β-cyclodextrin | 2.2–2.9 µm, studies performed on Sprague-Dawley rats | [61] | |
Ibuprofen | Chitosan | 2.1–2.7 µm | [62] | |
Plasmid DNA | Poly(D,L-lactic-co-glycolic) acid | Not mentioned | [63] | |
siRNA | Chitosan | <10 µm | [64] | |
5-fluorouracil | α-lactose monohydrate | Not mentioned | [65] | |
Curcumin | Hydroxypropyl-β-cyclodextrin | ~5.8 µm | [66] |
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Negi, A.; Nimbkar, S.; Moses, J.A. Engineering Inhalable Therapeutic Particles: Conventional and Emerging Approaches. Pharmaceutics 2023, 15, 2706. https://doi.org/10.3390/pharmaceutics15122706
Negi A, Nimbkar S, Moses JA. Engineering Inhalable Therapeutic Particles: Conventional and Emerging Approaches. Pharmaceutics. 2023; 15(12):2706. https://doi.org/10.3390/pharmaceutics15122706
Chicago/Turabian StyleNegi, Aditi, Shubham Nimbkar, and Jeyan Arthur Moses. 2023. "Engineering Inhalable Therapeutic Particles: Conventional and Emerging Approaches" Pharmaceutics 15, no. 12: 2706. https://doi.org/10.3390/pharmaceutics15122706
APA StyleNegi, A., Nimbkar, S., & Moses, J. A. (2023). Engineering Inhalable Therapeutic Particles: Conventional and Emerging Approaches. Pharmaceutics, 15(12), 2706. https://doi.org/10.3390/pharmaceutics15122706