Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention

Duret, Christophe; Merlos, Romain; Wauthoz, Nathalie; Sebti, Thami; Vanderbist, Francis; Amighi, Karim

doi:10.1016/j.ejpb.2013.03.005

Cited by 24 publications

(13 citation statements)

References 25 publications

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“…For some drugs with high water solubility and fast systemic absorption such as ciprofloxacin HCl, there may be a need to develop controlled released formulations to achieve high local drug concentrations for longer time (63). However, for poorly water soluble drugs, there is a need to improve the dissolution and maintain drug concentrations in the lung lining fluid above minimum inhibitory concentrations (16,64,65), particularly for azithromycin which has to enter the bacterial cells to be effective (34). Given lung surface is not an ideal place for drug dissolution due to the low fluid volume and particle clearance mechanisms (66), dissolution behavior is crucial for the efficacy of inhaled azithromycin DPIs.…”

Section: Discussionmentioning

confidence: 99%

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Mangal

Nie

et al. 2018

Pharm Res

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Purpose Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. Methods The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. Results The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. Conclusions We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.

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Section: Discussionmentioning

confidence: 99%

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Mangal

Nie

et al. 2018

Pharm Res

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“…However, we speculate that the turbulent airstream generated by the syringe due to this larger air volume may have led to the significantly higher powder deposition in the trachea due to inertial impaction. 44 We suspect while both dry powder NIMs and the liquid suspension impacted the tracheal walls, the liquid suspension flowed down the tracheal wall into the initial branches of the lung. This may have possibly led to less fluorescent dye and SPIONs observed in the trachea from the NIMs liquid suspension, as well as the apparent deposition of the iron in the unmagnetized lung lobes ( Figure 4 B).…”

Section: Discussionmentioning

confidence: 96%

In Vivo Pulmonary Delivery and Magnetic-Targeting of Dry Powder Nano-in-Microparticles

et al. 2017

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This brief communication evaluates the cytotoxicity and targeting capability of a dry powder chemotherapeutic. Nano-in-microparticles (NIMs) are a dry powder drug delivery vehicle containing superparamagnetic iron oxide nanoparticles (SPIONs) and either doxorubicin (w/w solids) or fluorescent nanospheres (w/v during formulation; as a drug surrogate) in a lactose matrix. In vitro cytotoxicity was evaluated in A549 adenocarcinoma cells using MTS and LDH assays to assess viability and toxicity after 48 h of NIMs exposure. In vivo magnetic-field-dependent targeting of inhaled NIMs was evaluated in a healthy mouse model. Mice were endotracheally administered fluorescently labeled NIMs either as a dry powder or a liquid aerosol in the presence of an external magnet placed over the left lung. Quantification of fluorescence and iron showed a significant increase in both fluorescence intensity and iron content to the left magnetized lung. In comparison, we observed decreased targeting of fluorescent nanospheres to the left lung from an aerosolized liquid suspension, due to the dissociation of SPIONs and nanoparticles during pulmonary administration. We conclude that dry powder NIMs maintain the therapeutic cytotoxicity of doxorubicin and can be better targeted to specific regions of the lung in the presence of a magnetic field, compared to a liquid suspension.

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“…ITZ, a poorly water‐soluble drug, was formulated as dry solid dispersion microparticles delivered by DPI . ITZ and saturated soybean PCs (phospholipon 90H®) were in amorphous state in crystalline mannitol matrix.…”

Section: Phospholipids As Pulmonary Excipientmentioning

confidence: 99%

“…A lung and systemic pharmacokinetic study in mice showed that the presence of saturated PCs in solid dispersion of ITZ (threefold in relation to ITZ weight) drastically increased the ITZ absorption through the lung epithelium in comparison to solid dispersion without saturated PCs (plasma C max of 352 ± 119 vs. 249 ± 54 ng/mL, with a plasma t max of 5 min vs. 30 min, respectively). Consequently, saturated PCs could increase the absorption of permeable drugs for systemic drug delivery but could decrease the drug lung residence for local drug delivery .…”

Section: Phospholipids As Pulmonary Excipientmentioning

confidence: 99%

Phospholipids in pulmonary drug delivery

Wauthoz

Amighi

2014

Euro J Lipid Sci & Tech

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Pulmonary delivery is becoming the standard route of administration for treating respiratory disorders such as asthma and chronic obstructive pulmonary disease. It is also gaining interest for non‐invasive systemic delivery of peptides and proteins. A limited number of excipients is approved or authorized for the pulmonary tract. This restricts the commercial potential of some formulations. Phospholipids and more particularly 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine (DPPC) are the main components of lung surfactant and are recognized as generally recognized as safe (GRAS) excipients for pulmonary drug delivery by the Food and Drug Administration. Moreover, phospholipids could modulate the physicochemical properties of drug delivery systems and therefore the drug release and/or dissolution. They can potentially modulate the drug pharmacokinetic by enhancing the drug permeability through the lung epithelium using palmitoyl‐based phospholipids, and/or by reducing recognition of the drug delivery systems by the alveolar macrophages by including DPPC or polyethyleneglycol (PEG) at their surface. Therefore, this review focuses on the formulations containing phospholipids or PEGylated phospholipids, such as micelles, liposomes, lipid micro‐/nanoparticles, large porous particles, solid dispersions, and microparticle suspensions. Drug delivery systems composed mainly or secondarily by phospholipids could be aerosolized by an appropriate device (nebulizer for aqueous‐based formulations, pressurized metered dose inhalers for propellant or aqueous‐based formulations or dry powder inhaler for powder‐based formulations) to be deposited in the lungs following their aerodynamic diameter. Phospholipids included in the drug delivery systems could modulate aerodynamic performances and drug pharmacokinetic.

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Pharmacokinetic evaluation in mice of amorphous itraconazole-based dry powder formulations for inhalation with high bioavailability and extended lung retention

Cited by 24 publications

References 25 publications

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

In Vivo Pulmonary Delivery and Magnetic-Targeting of Dry Powder Nano-in-Microparticles

Phospholipids in pulmonary drug delivery

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