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Among the different pulmonary fungal infections, aspergillosis, and in particular invasive pulmonary aspergillosis (IPA), are becoming the most worrying diseases in immunocompromised patients. This is due to their high incidence and mortality. Indeed, invasive aspergillosis manifests as invasive pulmonary disease accounting for 50/60% of all cases, with a mortality of 50-90% in severely immunocompromised patients. Triazoles act by inhibiting 14-α demethylase, a fungal cytochrome P450 enzyme implicated in the synthesis of ergosterol, an essential constituent of fungal cell walls. Moreover, they interact with the same cytochrome present in large quantities in the human liver, inducing possible drug-drug interactions in IPA patients. Consequently, interactions resulting from inhibitors, inductors, or substrates of cytochromes can modify the plasmatic concentrations of triazoles or other drugs administered concomitantly. To overcome these important issues, pulmonary delivery of triazoles could be an interesting alternative to conventional routes.The aim of this work was to develop triazole-based dry powders for inhalation able to be deposited adequately in the lungs, with a release of drug and a lung retention that can optimize its pharmacological action. This work focused on two active pharmaceutical ingredients (API): itraconazole (ITZ), for which improved solubility was needed, and voriconazole (VCZ), for which slow release was required.Concerning ITZ, solid dispersions for inhalation (SDIs) comprising ITZ and mannitol were previously developed in our laboratory. The selected SDI showed interesting results in terms of improved dissolution and lung retention in vivo in mice during a pharmacokinetic study. Therefore, this SDI was tested in a murine preclinical model of IPA and showed promising results in terms of prophylaxis efficacy. One aim of this work was to continue the pharmaceutical development of this promising SDI by making a scaling-up study. These methods we, Doctorat en Sciences biomédicales et pharmaceutiques (Pharmacie), info:eu-repo/semantics/nonPublished

Dry powders for inhalation with amorphous itraconazole (ITZ) dispersed in a hydrophilic matrix were previously obtained by the spray-drying technique. This gave interesting aerodynamic and dissolution characteristics leading to promising lung pharmacokinetic and prophylaxis efficacy in a preclinical model of invasive pulmonary aspergillosis. The spray-drying allows dry powder to be obtained in a one-step process; nonetheless, the scale-up still presents a challenge in maintaining the main particle characteristics. This study aimed to investigate the feasibility of obtaining similar powder characteristics from concentrated solutions using laboratory-scale and pilot-scale spray dryer equipment. ITZ was solubilized in a solvent mixture (ethanol/ethyl acetate/water mixture 40:40:20 v/v/v) in mannitol solutions or suspensions. These mixtures were spray dried at laboratory scale to produce a solid dispersion for inhalation (SDI) containing amorphous ITZ dispersed in a mannitol matrix. A solution of 35% (So1) w/w ITZ was chosen to evaluate the scale-up process. This formulation was chosen for its high yield (60%), its amorphous ITZ content (100%), its good aerodynamic behavior (fine particle fraction - FPF = 33± 2%) and its increased dissolution profile compared to bulk ITZ. The scale-up process showed pilot-scale dry powders with a higher yield than lab-scale dry powders and similar aerodynamic performance and equivalent dissolution profiles. Moreover, all SDIs displayed improved release kinetics in comparison with bulk ITZ. Despite the slight differences between lab- and pilot-scale SDIs, this study shows that the scaling-up process allowed interesting ITZ-based SDIs to be obtained, in order to achieve pilot-scale production., SCOPUS: ar.j, info:eu-repo/semantics/published

Pharmacokinetics of cisplatin administered by the pulmonary route were established in mice using dry powders inhaler (DPI) formulations showing immediate (F1) and controlled release (CR, solid lipid microparticles) in vitro, without (F2) or with PEGylated excipients (F3, F4). Formulation administration was realized using dry powder blends (correspondingly named thereafter F1B to F4B) able to reproducibly deliver particles in vivo using a DP-4M Dry Powder Insufflator™. Their platinum pharmacokinetics were established over 48 h in lungs, total blood and non-target organs vs. IV and endotracheal nebulization (EN). EN and F1B were rapidly distributed from the lungs (t1/2 i 2.6 and 5.0 min). F2B was eliminated in ∼1 h (t1/2 i 9.0 min). F3B lung retention was sustained for ∼7 h (t1/2 i 59.9 min), increasing lung AUC 11-, 4- and 3-fold vs. IV, F1B and F2B. Total blood tmax were higher and AUC and Cmax lower using the pulmonary route vs. IV. Kidney Cmax was reduced 6-, 2- and 3-fold for F1B, F2B and F3B. AUC in kidneys were 2- to 3-fold lower for F1B and F2B vs. IV but comparable for IV vs. F3B, probably because of kidney saturation. PEGylated solid lipid microparticles provided cisplatin particles with interesting lung retention and CR properties., SCOPUS: ar.j, info:eu-repo/semantics/published

The present study focuses on the development of dry powders for inhalation as adjuvant chemotherapy in lung cancer treatment. Cisplatin was chosen as a potential candidate for a local treatment as it remains the main platinum component used in conventional chemotherapies, despite its high and cumulative systemic toxicities. Bulk cisplatin was reduced to submicron sizes using high-pressure homogenization, mixed with a solubilized lipid and/or PEGylated component and then spray-dried to produce controlled-release dry powder formulations. The obtained formulations were characterized for their physicochemical properties (particle size and morphology), aerodynamic performance and release profiles. Cisplatin content and integrity were assessed by electrothermal atomic absorption spectrometry and 195Pt nuclear magnetic resonance spectroscopy. DPI formulations with cisplatin contents ranging from 48.5 to 101.0% w/w exhibited high fine particle fractions ranging from 37.3% to 51.5% of the nominal dose. Formulations containing cisplatin microcrystals dispersed in solid lipid microparticles based on acceptable triglycerides for inhalation and PEGylated excipients showed a controlled-release for more than 24 h and a limited burst effect. These new formulations could provide an interesting approach to increasing and prolonging drug exposure in the lung while minimizing systemic toxicities., SCOPUS: ar.j, info:eu-repo/semantics/published

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Three Itraconazole (ITZ) dry powders for inhalation (DPI) were prepared by spray-drying a mannitol solution in which the ITZ was in suspension (F1) or was in solution without (F2) or with phospholipid (PL) (F3). These powders were endotracheally insufflated in vivo at a single dose of 0.5mg/kg for pharmacokinetic profile (lung and plasma concentration) determination in ICR CD-1 mice. ITZ was crystalline in F1 and assumed to be amorphous in the F2 and F3 formulations. The amorphous nature of ITZ in F2 and F3 formulations allowed the in vitro formation of an ITZ supersaturated solution with a maximum solubility of 450±124ng/ml (F2) and 498±44ng/ml (F3), in contrast to formulation F1 (<10ng/ml). As a result of these higher solubilities, absorption into the systemic compartment after endotracheal administration was faster for formulations F2 and F3 (shorter tmax) and in larger quantities compared to the F1 formulation (plasmatic AUC0-24h of 182ngh/ml, 491.5ngh/ml and 376.8ngh/ml, and tmax of 60min, 30min and 5min for F1, F2 and F3, respectively). PL increased the systemic bioavailability of ITZ (determined by the AUCplasma to AUClung ratio) as a consequence of their wetting and absorption enhancement effect. ITZ lung concentrations after pulmonary administration remained higher than the targeted dose, based on the minimal inhibitory concentrations for Aspergillus Fumigatus (2μg/gwetlung), 24h post-administration for both F1 and F2 formulations. However, this was not the case for formulation F3, which exhibited a faster elimination rate from the lung, with an elimination half-life of 4.1h vs. 6.5h and 14.7h for F1 and F2, respectively., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: Efficient Itraconazole (ITZ) oral administration shows numerous limitations because of (i) the poor aqueous ITZ solubility inducing low and unpredictable bioavailability, (ii) the hepatic metabolism to an active metabolite and (iii) the large cytochrome inhibition increasing risks of drug-drug interactions. In case of pulmonary fungal infections, these issues increase the variability of plasmatic concentration in lungs to combat or prevent infection. ITZ pulmonary delivery would be an alternative by increasing ITZ concentration in the lungs while decreasing systemic exposure. Industrial production requires high solids/solutes concentration, using easily evaporable and non-flammable solvents (water, ethanol, isopropanol, ethyl acetate, etc.) while keeping dry powder properties obtained (particles size, residual moisture) at the laboratory scale to reach lungs but at a higher production scale.Materials and method: A screening of ITZ and mannitol solubility is performed on different organic solvent mixtures. Solid dispersions containing ITZ in mannitol matrix were obtained from solutions (So1, So2, and So3) or suspension (Su1) at 3.0% (So1, So3), 4.5% (So2) or 8% (Su1) (w/v) in the preferential organic solvent mixture. In the solutions, mannitol and 35% (So1, So2) or 60% (So3) of ITZ were dissolved. In the suspension, 10% of ITZ were dissolved and some particles of mannitol were suspended. The production method was the spray-drying using a B-290 Mini Spray Dryer (Büchi, Switzerland). The powders were characterized on their physico-chemical and aerodynamic properties (fine particle fraction - FPF), and on their dissolution profiles. Results: All the solid dispersion-based dry powders obtained after spray-drying showed no presence of crystalline ITZ (i.e. complete amorphous state). Because of drying of dissolved particles in the presence of undissolved mannitol particles, solid dispersion from the suspension presented median size (d(0.5)) bigger than solid, info:eu-repo/semantics/nonPublished

Invasive pulmonary aspergillosis (IPA) is a fungal infection that is seen with particular frequency in immunocompromised patients, and associated with high rates of mortality. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole have become accepted as first- and second-line therapy, respectively. However, triazoles are associated with issues of oral bioavailability, high liver metabolism, and/or drug–drug interactions, increasing the variability of systemic concentrations. As a way to overcome these issues, inhalation appears to be a promising route for delivery of triazoles for prophylactic or curative therapy in IPA. Indeed, pulmonary drug delivery drastically increases the drug in situ while decreasing the systemic exposure, thereby limiting drug metabolization, side effects, and drug–drug interactions. The development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but with significant different solubility. In this review, we describe the most advanced and promising pharmaceutical developments for voriconazole and itraconazole., SCOPUS: re.j, info:eu-repo/semantics/published

Invasive pulmonary aspergillosis (IPA) is a fungal infection that is seen with particular frequency in immunocompromised patients, and associated with high rates of mortality. To combat or prevent IPA, triazoles such as voriconazole or itraconazole and posaconazole have become accepted as first- and second-line therapy, respectively. However, triazoles are associated with issues of oral bioavailability, high liver metabolism, and/or drug–drug interactions, increasing the variability of systemic concentrations. As a way to overcome these issues, inhalation appears to be a promising route for delivery of triazoles for prophylactic or curative therapy in IPA. Indeed, pulmonary drug delivery drastically increases the drug in situ while decreasing the systemic exposure, thereby limiting drug metabolization, side effects, and drug–drug interactions. The development of triazoles for inhalation has focused on voriconazole and itraconazole, drugs which are both highly permeable but with significant different solubility. In this review, we describe the most advanced and promising pharmaceutical developments for voriconazole and itraconazole., SCOPUS: re.j, info:eu-repo/semantics/published

Introduction: Efficient Itraconazole (ITZ) oral administration shows numerous limitations because of (i) the poor aqueous ITZ solubility inducing low and unpredictable bioavailability, (ii) the hepatic metabolism to an active metabolite and (iii) the large cytochrome inhibition increasing risks of drug-drug interactions. In case of pulmonary fungal infections, these issues increase the variability of plasmatic concentration in lungs to combat or prevent infection. ITZ pulmonary delivery would be an alternative by increasing ITZ concentration in the lungs while decreasing systemic exposure. Industrial production requires high solids/solutes concentration, using easily evaporable and non-flammable solvents (water, ethanol, isopropanol, ethyl acetate, etc.) while keeping dry powder properties obtained (particles size, residual moisture) at the laboratory scale to reach lungs but at a higher production scale.Materials and method: A screening of ITZ and mannitol solubility is performed on different organic solvent mixtures. Solid dispersions containing ITZ in mannitol matrix were obtained from solutions (So1, So2, and So3) or suspension (Su1) at 3.0% (So1, So3), 4.5% (So2) or 8% (Su1) (w/v) in the preferential organic solvent mixture. In the solutions, mannitol and 35% (So1, So2) or 60% (So3) of ITZ were dissolved. In the suspension, 10% of ITZ were dissolved and some particles of mannitol were suspended. The production method was the spray-drying using a B-290 Mini Spray Dryer (Büchi, Switzerland). The powders were characterized on their physico-chemical and aerodynamic properties (fine particle fraction - FPF), and on their dissolution profiles. Results: All the solid dispersion-based dry powders obtained after spray-drying showed no presence of crystalline ITZ (i.e. complete amorphous state). Because of drying of dissolved particles in the presence of undissolved mannitol particles, solid dispersion from the suspension presented median size (d(0.5)) bigger than solid, info:eu-repo/semantics/nonPublished

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The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M®) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

The aim of this study was to evaluate the ability of the Penn-Century Dry Powder Insufflator for mice (DP-4M®) to reproducibly, uniformly, and deeply deliver dry powders for inhalation in the mouse lung. Itraconazole-based dry powder formulations produced by spray-drying were different in terms of composition (different ratios of drug and mannitol, with or without phospholipids), but relatively similar in terms of particle size and mass median aerodynamic diameter. The ability of the dry powder insufflator to disaggregate each formulation was the same, indicated by the absence of a statistically significant difference between the particle size distribution parameters, as measured by laser scattering. The emitted fraction varied in vivo compared to the in vitro condition. Fluorescent particle distribution in the lungs was uniform and reached the alveolar spaces, as visualized by fluorescent microscopy. In terms of drug recovery in lung tissue, a minimum administered powder mass (in this case ∼1mg) was necessary to recover at least 30% of the emitted dose in the lung and to obtain reproducible pulmonary concentrations. To reduce the dose administered in the lung, it was preferable to dilute the active ingredient within the carrier instead of reducing the dry powder mass inserted in the sampling chamber. Dry powder insufflators are devices usable in dose-dependent preclinical trials but have critical parameters to efficiently deliver reproducible doses depending on the type of formulation., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published