Formulation of Dry Powders for Inhalation Comprising High Doses of a Poorly Soluble Hydrophobic Drug

Tarara, Thomas E.; Miller, Danforth P.; Weers, Audrey E.; Muliadi, Ariel R.; Tso, Jerry; Eliahu, Avi; Weers, Jeffry G.

doi:10.3389/fddev.2022.862336

Cited by 12 publications

(4 citation statements)

References 50 publications

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“…In the design of medical devices that interact with bodily fluids, hydrophobic surfaces can reduce the risk of biofilm formation and infection, while hydrophilic surfaces can improve lubricity and ease of insertion [42,43]. Moreover, hydrophilic characteristics can also be used to enhance drug loading and release, while hydrophobic coatings can increase drug stability and reduce degradation [44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Wetting behavior of stainless-steel surface with zinc oxide nanorod coatings: modulations in nanorod alignment through atomic layer deposition

Kim,

Hong,

Song

2024

Nanotechnology

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This study investigated the hydrophobic-hydrophilic characteristics of zinc oxide (ZnO) nanorod coatings for potential biomedical applications. We examined the effects of different alignments of ZnO nanorods on the wetting and mechanical characteristics of the coatings.ZnO seed layers were prepared on stainless-steel plates using atomic layer deposition (ALD) at five different temperatures ranging from 50 to 250 ℃. The ZnO nanorod coatings were then deposited on these seed layers through chemical bath deposition. The polycrystalline structure of the seed layers and the morphology of the nanorods were analyzed using grazing incidence angle X-ray diffraction, transmission electron microscopy, and scanning electron microscopy. Mechanical and wetting properties of the nanorod coatings were examined using nanoindentation and water-droplet tests. The seed layers produced at 50 and 250 ℃ showed stronger (0 0 2) peaks than the other layers. ZnO nanorods on these seed layers exhibited greater vertical orientation and lower water contact angles indicating a more hydrophilic surface. Additionally, vertically oriented nanorod coatings demonstrated greater elastic modulus and hardness than those of oblique nanorods. Our findings indicate that ALD technology can be used to control the spatial arrangement of ZnO nanorods and optimize the hydrophobic-hydrophilic and mechanical properties of coating surfaces.

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Section: Introductionmentioning

confidence: 99%

Wetting behavior of stainless-steel surface with zinc oxide nanorod coatings: modulations in nanorod alignment through atomic layer deposition

Kim,

Hong,

Song

2024

Nanotechnology

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“…26−28 However, this only applies when no active metabolites are formed. Based on the absence of basic nitrogen(s) in the chemical structures of PF-06263276 29 (1), GDC-4379 30,31 (5), KN-002 (6, presumed structure, formerly VR588), 32−35 and AZD0449 (7) 36 of Figure 1, a crude assessment is that the lung retention driver may be solubility and/or low dissolution rate. Correspondingly, for those molecules having basic nitrogen, that is, TD-8236 (2, presumed structure), 37,38 nezulcitinib 39,40 (3), iJak-381 28 (4), and LAS194046 (8), 41,42 some degree of lung tissue affinity may aid their lung retention.…”

Section: ■ Introductionmentioning

confidence: 99%

“…As has been suggested, possible lung retention strategies include (i) lowering intrinsic solubility, (ii) limiting the dissolution rate, (iii) lowering the permeability, and (iv) increasing the lung tissue affinity. , Furthermore, minimizing systemic exposure by high clearance from the systemic circulation is an attractive strategy. − However, this only applies when no active metabolites are formed. Based on the absence of basic nitrogen(s) in the chemical structures of PF-06263276 ( 1 ), GDC-4379 , ( 5 ), KN-002 ( 6 , presumed structure, formerly VR588), − and AZD0449 ( 7 ) of Figure , a crude assessment is that the lung retention driver may be solubility and/or low dissolution rate. Correspondingly, for those molecules having basic nitrogen, that is, TD-8236 ( 2 , presumed structure), , nezulcitinib , ( 3 ), iJak-381 ( 4 ), and LAS194046 ( 8 ), , some degree of lung tissue affinity may aid their lung retention.…”

Section: Introductionmentioning

confidence: 99%

Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

Nilsson,

Berggren,

Berglund

et al. 2023

J. Med. Chem.

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JAK-STAT cytokines are critical in regulating immunity. Persistent activation of JAK-STAT signaling pathways by cytokines drives chronic inflammatory diseases such as asthma. Herein, we report on the discovery of a highly JAK1-selective, ATP-competitive series of inhibitors having a 1000-fold selectivity over other JAK family members and the approach used to identify compounds suitable for inhaled administration. Ultimately, compound 16 was selected as the clinical candidate, and upon dry powder inhalation, we could demonstrate a high local concentration in the lung as well as low plasma concentrations, suggesting no systemic JAK1 target engagement. Compound 16 has progressed into clinical trials. Using 16, we found JAK1 inhibition to be more efficacious than JAK3 inhibition in IL-4-driven Th2 asthma.

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“…In contrast, spray drying with polysaccharide excipients, especially dextran (Dex), has been reported to result in porous particles with a hydrophobic surface (Kadota et al, 2019;Tarara et al, 2022), which is a critical quality attribute for high aerosol performance. However, there are no studies on the use of Dex as a stabilizing agent in combination with the anti-adherent Leu for pulmonary delivery.…”

Section: Introductionmentioning

confidence: 99%

Inhalable Composite Microparticles Containing siRNA-Loaded Lipid-Polymer Hybrid Nanoparticles: Saccharides and Leucine Preserve Aerosol Performance and Long-Term Physical Stability

Turan

Shi

et al. 2022

Front. Drug. Deliv.

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Thermostable dry powder formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of lung diseases. However, preserved long-term physical stability of dry powder inhaler (DPI) formulations is critical to ensure efficient and reproducible delivery to the airways during the shelf life of the drug product. Here, we show that ternary excipient mixtures of the disaccharide trehalose (Tre), the polysaccharide dextran (Dex), and the shell-forming dispersion enhancer leucine (Leu) stabilize siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) during spray drying into nanocomposite microparticles, and result in inhalable solid dosage forms with high aerosol performance and long-term stability. The stabilizing roles of Tre and Dex were also studied separately by investigating DPI formulations containing binary mixtures of Leu/Tre and Leu/Dex, respectively. DPI formulations containing binary Leu/Dex mixtures were amorphous and displayed preserved long-term physical stability of LPNs and chemical stability of siRNA in accelerated stability studies under exaggerated storage conditions (ambient temperature and relative humidity). In contrast, powders containing binary Leu/Tre mixtures were amorphous, and hence metastable, and were recrystallized after six months of storage. Ternary mixtures of Tre, Leu, and Dex provided the most efficient protection of the LPNs during the spray drying process and prevented recrystallization of amorphous Tre. Hence, in ternary mixtures, Leu, Tre, and Dex have the following functions: the shell-forming Leu functions as a dispersion enhancer and is essential for high aerosol performance, the disaccharide Tre provides LPN protection during manufacturing and storage due to efficient coverage of the LPN surface, and the polysaccharide Dex promotes the formation of porous particles and prevents recrystallization of Tre during long-term storage. Therefore, the use of ternary excipient mixtures composed of Leu, Tre, and Dex, may prevent instability problems of DPI formulations and preserve the aerosol performance during long-term storage, which is essential for effective pulmonary drug delivery.

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Formulation of Dry Powders for Inhalation Comprising High Doses of a Poorly Soluble Hydrophobic Drug

Cited by 12 publications

References 50 publications

Wetting behavior of stainless-steel surface with zinc oxide nanorod coatings: modulations in nanorod alignment through atomic layer deposition

Wetting behavior of stainless-steel surface with zinc oxide nanorod coatings: modulations in nanorod alignment through atomic layer deposition

Discovery of the Potent and Selective Inhaled Janus Kinase 1 Inhibitor AZD4604 and Its Preclinical Characterization

Inhalable Composite Microparticles Containing siRNA-Loaded Lipid-Polymer Hybrid Nanoparticles: Saccharides and Leucine Preserve Aerosol Performance and Long-Term Physical Stability

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