The influence of the size and morphology of carrier particles on drug dispersion performance from passive dry powder inhalers has been extensively studied topic, and a consensus has been reached regarding the adverse effect that larger carrier particle diameters impart to aerosol performance. However, previous studies have generally employed only a few carrier particle size fractions, generally possessing similar surface characteristics. Accordingly, theories developed to explain the influence of the physical characteristics of carrier particles on performance relied heavily on both extrapolation and interpolation. To fill in the gaps from the literature and simultaneously evaluate the influence of carrier particle size and morphology, a comprehensive study was undertaken using 4 lactose grades, each sieved into 13 contiguous sizes, to prepare 52 formulations incorporating a unique lactose grade-size population. The aerosol performance results indicated that large carrier particles possessing extensive surface roughness can improve drug dispersion, in contrast to what has been previously reported. It is proposed that this may be attributed to mechanical detachment forces arising from collisions between the carrier particle and inhaler during actuation. Based on these observations, a novel dry powder inhaler platform was developed, employing carrier particles much larger (> 1 mm) than previously explored in both the scientific and patent literature. Optimization of this technology required the judicious selection of a carrier material, and following an extensive screening process, low-density polystyrene was selected as a model candidate. Given its low mass, diameters in excess of 5-mm could be employed as carriers while still generating high detachment forces. To minimize drug particle aggregation, a novel drug-coating method employing piezo-assisted particle dispersion was developed to compensate for the reduced surface area of the novel carrier particles. In addition, the selection of a suitable inhalation device prototype was instrumental to the overall performance of the technology. In vitro testing of the novel large carrier particles yielded emitted fractions in excess of 85%, and overall drug delivery of up to 69% of the nominal dose. / text

The aim of this research was to develop and fully investigate a novel method of antibiotic drug delivery to the lung that will address problems with current therapeutic regimens for treatment of airway infections. To demonstrate the performance of prepared formulations, the design of suitable characterization methods were also aimed. A novel dissolution method for evaluating the in vitro dissolution behavior of inhalation formulations was developed. The membrane holder was designed to enclose previously air-classified formulations so that they could be uniformly tested in the dissolution apparatus. Dissolution procedures, the apparatus, the dose collection, the medium, and test conditions were developed and the dissolution behaviors of test compounds were evaluated by experimental and mathematical analysis. It was proved that the aerodynamic separation of formulation prior to dissolution assessment have a significant influence on the dissolution profiles. The optimized test method using the membrane holder was applied to evaluate in vitro dissolution profiles of the manufactured formulations of rifampicin (RF). The carrier/excipient-free RF dry powder formulation was investigated. The rifampicin dihydrate (RFDH) powders having MMAD of 2.2 um were prepared using a simple recrystallization process. The RFDH powders have a thin flaky structure, and this unique morphology provides improved aerosolization properties at maximal API loading. The manufactured RFDH formulation showed 80% drug release within 2 hours. To retard the release rate of RF, the prepared RFDH crystals were coated with hydrophobic polymer, PLA or PLGA, using spray-dryer equipped with multi-channel spray nozzles. The multi-channel spray nozzle used in this study has two separate nozzles for aqueous solution and one for gas fluid. The RFDH crystals and the coating solutions were sprayed through the two separate liquid nozzles at the same time. The coated RFDH formulations were prepared using multi-channel spray nozzles. The coated formulations contained at least 50% w/w of RF with no change of their flaky morphology. The initial RF release was lowered by coating; the lowest initial RF release was observed from the coated powders with PLA polymer as 32% among the coated formulations. Overall, the 80% of RF was released within 8 hours. The RFDH and coated RFDH formulations delivered via the pulmonary route would be anticipated to provide higher local (lung) drug concentrations than that of orally delivered powders. Particularly, the coated RFDH powders deposited in the alveolar region may prolong the drug residence time in the site of infections. Additionally, it was proved that the RFDH and coated RFDH formulations provided much better stability than the amorphous RF. / text

Chronic respiratory diseases such as asthma, COPD, pulmonary fibrosis are more prevalent throughout the world. For some of these diseases there is no cure, the current treatment options manages the symptoms and acute exacerbation. The new approach to find a curative therapy for respiratory diseases is by targeting the cellular / molecular pathways that either cause the disease or has the potential cure the disease. It becomes important to target the respiratory system in treating these diseases to increase the delivered dose and reduce the unwarranted adverse effects. Dry powder inhaler (DPI) is a targeted drug delivery dosage form commonly used to target the airways to treat respiratory diseases. There are two components to dry powder inhaler product – powdered drug formulation and inhaler device; a unified performance of the two is essential for a successful product. In this study, dry powder aerosol of novel drug compounds that targets the underlying cellular and molecular mechanism are developed for the first time. Advanced organic closed mode spray drying technique was used to the produce microparticulate/ nanoparticulate formulations. The formulation of the novel compounds involved utilizing sugar based excipients. Each formulation that was produced was comprehensively characterized in the solid state. The safety of these formulations were tested in in vitro human pulmonary cell lines. The in vitro aerosol dispersion of the spray dried drugs were tested using three FDA approved human inhaler devices. The influence of the inhaler device resistance and spray drying process conditions on the aerosol dispersion was evaluated. Preliminary testing of the formulations in in vivo animal models shows promising results in treating chronic respiratory diseases with these superior aerosol formulations.

No / The ability to generate predictive models linking the in vitro assessment of pharmaceutical products with in vivo performance has the potential to enable greater control of clinical quality whilst minimizing the number of in vivo studies in drug development. Artificial neural networks (ANNs) provide a means of generating predictive models correlating critical product characteristics to key performance attributes. In this regard, ANNs have been used to model historical data exploring the relative lung bioavailability of salbutamol from several different nebulizers. The generated ANN model was shown to relate urinary salbutamol excretion at 30 min postinhalation, which is the index of relative lung bioavailability of salbutamol, to specific fractions of the particle size distribution, to subject body surface area and to the methods of nebulization. This model was validated using unseen data and gave good agreement with pharmacokinetic outcomes for 17 data records. The model gave improved predictions of urinary salbutamol excretion for individual subjects compared to the published linear correlation generated using the same data. It is therefore concluded that ANN models have the potential to provide reliable estimates of pharmacokinetic performance that relate to lung deposition, for nebulized medicines in individual subjects.

La pyrazinamide est le seul anti-tuberculeux de première intention actif sur la formedormante de Mycobacterium tuberculosis. Sa prescription par voie orale permet de réduire la durée du traitement de 9 à 6 mois. Nous avons développé des formes galéniques de pyrazinamide administrables directement au niveau des poumons afin d'augmenter localement la concentration de pyrazinamide au site pathologique afin de réduire la durée du traitement. Deux formes galéniques de pyrazinamide ont été optimisées: une poudre sèche pour inhalation et des nanoparticules polymères administrables par nébulisation liquide ou sous forme de poudre sèche.La poudre sèche pour inhalation est composée de particules obtenues par atomisation-séchage. La pyrazinamide a été solubilisée dans un mélange 70/30 v/véthanol/eau. Après atomisation-séchage de cette solution, nous avons obtenu des particules cristallines instables et non adaptées à l'administration pulmonaire du fait de leur grande taille. Afin d'obtenir des poudres adaptées à une administration pulmonaire dans le poumon profond, et stables en termes de taille et de caractéristiques physico-chimiques, nous avons passé en revue toute une série d'excipients: phospholipides, bicarbonate d'ammonium, leucine, acide hyaluronique.Nous avons montré qu'en associant tous ces excipients au principe actif, on pouvait obtenir des particules d'environ 6 microns, de faible densité tassée et stables pendant 4 semaines dans des conditions de stockage classiques.L'évaluation aérodynamique in vitro de la poudre optimisée a révélé l'existence de deux populations de particules: de grosses particules pauvres en pyrazinamide et de petites particules riches en pyrazinamide. Ces deux populations proviennent d'une ségrégation des différents composants lors du processus de séchage. Pour remédier à ce phénomène et obtenir des particules de composition homogène, la vitesse de séchage a été diminuée. En conséquence, nous avons obtenu des poudres homogènes avec de bonnes propriétés aérodynamiques pour délivrance dans les poumons: fraction de particules fines de 40,1 ± 1,0% et fraction alvéolaire de 29,6 ±3,1%. Cette poudre a alors été évaluée in vivo chez le rat sain et nous avons mesuré les concentrations de pyrazinamide dans le plasma et le liquide de lavage bronchoalvéolaire après insufflation intratrachéale de la poudre, par comparaison avec une administration intraveineuse d'une solution de pyrazinamide. L'insufflation intratrachéale de poudre et l'administration intraveineuse conduisent à des paramètres pharmacocinétiques similaires prouvant que les particules se dissolvent rapidement lors du dépôt et que la molécule traverse efficacement la barrière pulmonaire pour atteindre la circulation systémique. De manière surprenante, la pyrazinamide est éliminée plus rapidement du liquide pulmonaire lorsqu'elle est administrée par insufflation intratrachéale que par voie intraveineuse. La délivrance pulmonaire de pyrazinamide apparaît comme une alternative intéressante à l'administration orale de la molécule et doit maintenant être testée dans un modèle d'animal infecté pour évaluer son efficacité contre Mycobacterium tuberculosis.En parallèle, nous avons optimisé l'encapsulation de pyrazinamide dans des nanoparticules polymères de poly(lactide-co-glycolide) PLGA monodisperses de taille inférieure à 200nm, grâce un plan d'expériences. Les nanoparticules de PLGA chargées en pyrazinamide ont été préparées par la méthode d'émulsion double. La méthode de Taguchi a été utilisée pour optimiser les paramètres de formulation. Le type de solvant, le rapport en poids pyrazinamide/ PLGA et le rapport des volumes des phases aqueuse et organique étaient les paramètres pertinents. La méthode de Taguchi s'est avérée efficace pour optimiser les nanoparticules d'environ 170nm avec un indice de polydispersité ˂ 0,1, un potentiel zêta d'environ -1mV et une efficacité d'encapsulation de 7-8% soit 3% de taux de charge de la pyrazinamide. / Pyrazinamide is the only first intention anti-TB drug active on the dormant form ofMycobacterium tuberculosis. Its oral prescription reduces treatment duration from 9to 6 months. We have developed dosage forms of pyrazinamide to administer directlyto the lungs to locally increase the concentration of pyrazinamide at the diseased siteand further reduce the duration of treatment. Two dosage forms of pyrazinamidewere optimized: a dry powder for inhalation and polymer nanoparticles administrableeither by liquid nebulization or as a dry powder.The dry powder for inhalation is composed of particles obtained by spray-drying.Pyrazinamide was dissolved in a mixture 70/30 v/v ethanol/water. After spray-dryingthe solution, we obtained large crystalline particles that were unstable and notsuitable for pulmonary administration because of their large sizes. To obtain powderssuitable for pulmonary delivery to the deep lungs, and stable in terms of size andphysico-chemical characteristics, we reviewed a variety of excipients: phospholipids,ammonium bicarbonate, leucine, hyaluronic acid. We have shown that by combiningall these excipients with the drug, one could obtain particles of about 6 microns, witha low tapped density and stable for 4 weeks under conditions of conventionalstorage.The in vitro aerodynamic evaluation of the optimized powder showed the existence oftwo populations of particles: large particles with a low content of pyrazinamide andsmall particles with high pyrazinamide content. These two populations derived fromthe segregation of different components during the drying process. To obtainparticles of uniform composition, the drying rate was decreased. As a result, weobtained homogeneous powders with good aerodynamic properties for delivery intothe lungs: fine particle fraction of 40.1 ± 1.0% and alveolar fraction of 29.6 ± 3.1%.This powder was then evaluated in vivo in healthy rats and we measured theconcentrations of pyrazinamide in plasma and bronchoalveolar lavage fluid afterintratracheal insufflation of the powder in comparison with intravenous administrationof a solution of pyrazinamide. The intratracheal insufflation of the powder and theintravenous injection lead to similar pharmacokinetic parameters proving that theparticles dissolve rapidly after deposition and pyrazinamide crosses efficiently thelung barrier to reach the systemic circulation. Surprisingly, pyrazinamide disappears4faster form lung lining fluid when administered by pulmonary insufflation than afterintravenous administration. Pulmonary delivery of pyrazinamide appears as anattractive alternative to oral administration of the drug and must now be tested in ananimal model of infection to assess its efficacy against Mycobacterium tuberculosis.In parallel, we have optimized the encapsulation of pyrazinamide in polymericnanoparticles of poly (lactide-co-glycolide) PLGA lower than 200 nm andmonodisperse, using experimental design. The pyrazinamide-loaded PLGAnanoparticles were prepared by the double emulsion method. The Taguchi methodwas used to optimize the formulation parameters. The type of solvent, thepyrazinamide / PLGA weight ratio and aqueous to organic phases volume ratio wererelevant parameters. The Taguchi method has proven effective to optimizenanoparticles of about 170nm with a polydispersity index < 0.1, a zeta potential ofapproximately -1mV and an encapsulation efficiency of 7-8% or 3% pyrazinamide drugloading.

Today, orally inhaled drugs found on the market suffer from variable and discontinuous pulmonary drug release which lowers efficacy and patience compliance. This is usually a consequence of the poor understanding of the interaction and dissolution behavior of drug particles in the lung environment. Thus, the aim of this project was to investigate the effect of the dissolution medium on dissolution profiles for the well-known orally inhaled drug budesonide (BD) and fluticasone propionate (FP), in order to assess the importance of a proper selection of dissolution media for in vitro dissolution methods. In order to achieve this a modified Andersen Cascade Impactor was used to simulate deposition of particles onto filters. The dissolution was measured using a Transwell set up with polycarbonate membranes that can hold the filters with the deposited drug on it. Different media were prepared, from simple to more biorelevant. The samples taken during the dissolution experiments were analyzed quantitatively using UPLC-UV and the experimental data was processed by fitting to the Weibull function. The aim of this project was successfully achieved and the dissolution media that worked best for both BD and FP was PBS with the addition of 0.5% SDS. On the other hand, the dissolution media that performed the least for both BD and FP was the simulated lung fluid (SLF) with presence of 0.02% (w/v) DPPC. This may be due to the fact that DPPC forms liposomal aggregates which probably results in the media becoming more viscous and hence the dissolution time becomes slower.