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.

When it comes to dry powder inhalation (DPI), adhesive mixtures are the most widely used formulation type. Various techniques have been developed to generate inhaled drug particles and improve the delivery efficiency of DPI formulations. For dry powder inhaler formulations (DPIs), micronized drug powders are usually mixed with lactose carriers to improve powder handling during manufacturing and powder aerosol delivery during patient use. The performance of DPI systems is strongly dependent on several formulation factors, the construction of the delivery device and the inhalation technique. There is a growing interest in DPI in new medical areas such as vaccines and antibiotics which requires further development and challenges to ensure physical and aerosolization stability of DPI.  This project aims to discuss the development of inhalation therapy, the challenges during formulation processes, the mixing process and the use of excipients in pulmonary drug delivery in DPIs. Further, the project is covered by experiments based on the literature overview and performed at the Department of Pharmaceutical Biosciences at Uppsala University. Bulk density was measured on three series of adhesive mixtures with increasing amounts of fine particles. In two series, small amounts of Magnesium Stearate, 0,1% and 0,01% were added.

No / In vitro dissolution testing as a form of quality control has become a necessity in the pharmaceutical industry. As such, the need to establish a method that investigates the in vitro dissolution profile of inhaled products should be taken into account. The prime focus in this study was to examine the in-vitro in-vivo correlation utilising a modified version of the Twin Stage Impinger and to promote an in vitro dissolution model by enhancing the Fine Particle Dose (FPD) collection method for dry powder inhalers. The Twin Impinger was modified by inserting a stainless steel membrane holder disk in the base of the lower chamber. The design, with optimum drug deposition, was adopted for the dissolution study of budesonide and salbutamol. Afterwards, the membrane holder system was placed in the bottom of the dissolution vessel. Phosphate buffer saline (PBS), simulated lung fluid (SLF, Gamble solution) and Phosphate buffer (PB) were used in the study. The paddle dissolution apparatus, containing 300 mL of the medium, was operated at 75 rpm paddle speed. Samples were collected at defined time intervals and analysed using a validated HPLC method. The largest proportion of the budesonide dose was dissolved in PBS compared to PB and SLF. This was due to the presence of surfactant (0.2% w/v polysorbate), which enhances the wettability and the solubility of the poorly soluble drug (budesonide). The similarity factors for PBS and PB were 47.6 and 69.7, respectively, using SLF as a reference, whereas the similarity factor for salbutamol dissolution between PB and SLF was 81.3, suggesting PB is a suitable substitute. Comparison using both the predicted and actual in vivo pharmacokinetics (PK) values of the two drugs, as well as the pattern of their Concentration-Time (c-t) profiles, showed good similarity, which gave an indication of the validity of this in vitro dissolution method.

Curcuminoids have strong anticancer activities but have low bioavailability. The highest rate of cancer deaths comes from lung tumours; therefore, inhaled curcuminoids could treat lung cancer locally. To date, there are no nebulised formulations of curcuminoids, and there are no inhalable curcuminoids particles without excipients using air jet mill and sonocrystallisation methods for DPI formulations. It is the first time; the aerodynamic parameters of curcumin, demethoxycurcumin and bisdemethoxycurcumin were measured individually using NGI. The size, shape, free surface energy, and the crystal polymorphism of the produced inhalable curcuminoid particles were characterised using laser diffraction, SEM, IGC, DSC and XRPD, respectively. Several DPI formulations with a variable particle size of curcuminoids were prepared in two drug-carrier ratios (1:9 and 1:67.5). The best performance of the DPI formulations of the sonocrystallised particles, which exist in crystal structure form1, were obtained from ethanol- heptane, as illustrated FPF 43.4%, 43.6% and 43.4% with MMAD of 3.6µm, 3.5µm and 3.4µm, whereas the best DPI formulation of the air jet milled particles was presented FPF 38.0%, 38.9%, and 39.5% with MMAD of 3.6µm, 3.4µm and 3.2µm for curcumin, demethoxycurcumin and bisdemethoxycurcumin, respectively. Nebulised curcuminoids using nanoemulsion and microsuspension formulations were prepared. The physical properties, such as osmolality, pH and the viscosity of the aerosolised nanoemulsion and the microsuspension formulations were determined. The FPF% and MMAD of nebulised nanoemulsion ranged from 44% to 50% and from 4.5µm to 5.5µm respectively. In contrast, the FPF% of microsuspension ranged from 26% to 40% and the MMAD from 5.8µm to 7.05µm. A HPLC method was developed and validated in order to be used in the determination of curcuminoids from an aqueous solution.

Dry Powder Inhalers (DPIs) have great potential in pulmonary drug delivery; the granular powder, used as active ingredient in DPIs, is ozone friendly and the operation of DPIs ensures coordination between dose release and patient inhalation. However, the powder fluidisation mechanisms are poorly understood which leads to low efficiency of DPIs with 10-35 % of the dose reaching the site of action. The main aim of this thesis is to study the hydrodynamics of powder fluidisation in DPIs, using experimental and computational approaches. An experimental test rig was developed to replicate the process of transient powder fluidisation in an impinging air jet configuration. The powder fluidisation chamber was scaled up resulting in a two dimensional particle flow prototype, which encloses 3.85 mm glass beads. Using optical image processing techniques, individual particles were detected and tracked throughout the experimental time and domain. By varying the air flow rate to the test section, two particle fluidisation regimes were studied. In the first fluidisation regime, the particle bed was fully fluidised in less than 0.25 s due to the strong air jet. Particle velocity vectors showed strong convective flow with no evidence of diffusive motion triggered by inter-particle collisions. In the second fluidisation regime, the particle flow experienced two stages. The first stage showed strong convective flow similar to the first fluidisation regime, while the second stage showed more complex particle flow with collisional and convective flow taking place on the same time and length scales. The continuum Two Fluid Model (TFM) was used to solve the governing equations of the coupled granular and gas phases for the same experimental conditions. Sub-models for particle-gas and particle-particle interactions were used to complete the model description. Inter-particle interactions were resolved using models based on the kinetic theory of granular flow for the rapid flow regime and models based on soil mechanics for the frictional regime. Numerical predictions of the first fluidisation regime showed that the model should incorporate particle-wall friction and minimise diffusion, simultaneously. Ignoring friction resulted in fluidisation timing mismatch, while increasing the diffusion resulted in homogenous particle fluidisation in contrast to the aggregative convective fluidisation noticed in the experiments. Numerical predictions of the second fluidisation regime agreed well with the experiments for the convection dominated first stage of flow up to 0.3 s. However, later stages of complex particle flow showed qualitative discrepancies between the experimental and the computational approaches suggesting that current continuum granular models need further development. The findings of the present thesis have contributed towards better understanding of the mechanics of particle fluidisation and dense multiphase flow in DPI in particular, and particle bed fluidisation using impinging air jet in general. The use of TFM for predicting high speed convective granular flows, such as those in DPIs, is promising. Further studies are needed to investigate the form of particle-particle interactions within continuum granular flow models.

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The full text will be available at the end of the embargo: 9th May 2024

The overall objectives of this research project were i) to develop and evaluate methods of characterizing nasal spray products using realistic nasal airway models as more clinically relevant in vitro tools and ii) to develop and evaluate a novel high-efficiency antibiotic nanoparticle dry powder formulation and delivery device. Two physically realistic nasal airway models were used to assess the effects of patient-use experimental conditions, nasal airway geometry and formulation / device properties on the delivery efficiency of nasal spray products. There was a large variability in drug delivery to the middle passages ranging from 17 – 57 % and 47 – 77 % with respect to patient use conditions for the two nasal airway geometries. The patient use variables of nasal spray position, head angle and nasal inhalation timing with respect to spray actuation were found to be significant in determining nasal valve penetration and middle passage deposition of Nasonex®. The developed test methods were able to reproducibly generate similar nasal deposition profiles for nasal spray products with similar plume and droplet characteristics. Differences in spray plume geometry (smaller plume diameter resulted in higher middle passage drug delivery) were observed to have more influence on regional nasal drug deposition than changes to droplet size for mometasone furoate formulations in the realistic airway models. Ciprofloxacin nanoparticles with a mean (SD) volume diameter of 120 (10) nm suitable for penetration through mucus and biofilm layers were prepared using sonocrystallization technique. These ciprofloxacin nanoparticles were then spray dried in a PVP K30 matrix to form nanocomposite particles with a mean (SD) volume diameter of 5.6 (0.1) µm. High efficiency targeted delivery of the nanocomposite nasal powder formulation was achieved using a modified low flow VCU DPI in combination with a novel breathing maneuver; delivering 73 % of the delivered dose to the middle passages. A modified version of the nasal airway model accommodating Transwell® inserts and a Calu-3 monolayer was developed to allow realistic deposition and evaluation of the nasal powder. The nanocomposite formulation was observed to demonstrate improved dissolution and transepithelial transport (flux = 725 ng/h/cm2) compared to unprocessed ciprofloxacin powder (flux = 321 ng/h/cm2).

This research was aimed at the development and validation of new in vitro methods capable of predicting in vivo drug deposition from dry powder inhalers, DPIs, in lung-normal human adults. Three physical models of the mouth, throat and upper airways, MT-TB, were designed and validated using the anatomical literature. Small, medium and large versions were constructed to cover approximately 95% of the variation seen in normal adult humans of both genders. The models were housed in an artificial thorax and used for in vitro testing of drug deposition from Budelin Novolizer DPIs using a breath simulator to mimic inhalation profiles reported in clinical trials of deposition from the same inhaler. Testing in the model triplet produced results for in vitro total lung deposition (TLD) consistent with the complete range of drug deposition results reported in vivo. The effect of variables such as in vitro flow rate were also predictive of in vivo deposition. To further assess the method’s robustness, in vitro drug deposition from 5 marketed DPIs was assessed in the “medium” MT-TB model. With the exception of Relenza Diskhaler, mean values for %TLD+SD differed by only < 2% from their literature in vivo. The relationship between inhaler orientation and in vitro regional airway deposition was determined. Aerosol drug deposition was found to depend on the angle at which an inhaler is inserted into the mouth although the results for MT deposition were dependent on both the product and the formulation being delivered. In the clinic, inhalation profiles were collected from 20 healthy inhaler naïve volunteers (10M, 10F) before and after they received formal inhalation training in the use of a DPI. Statistically significant improvements in Peak Inhalation Flow Rate (PIFR) and Inhalation Volume (V) were observed following formalized training. The shapes of the average inhalation profiles recorded in the clinic were found to be comparable to the simulated profiles used in the in vitro deposition studies described above. In conclusion, novel in vitro test methods are described that accurately predict both the average and range of aerosol airway drug deposition seen from DPIs in the clinic.

The aim of the work was to design, manufacture, and characterize targeted multi-component dry powder aerosols of (non-destructive) mucolytic agent (mannitol), antimicrobial drug (tobramycin or azithromycin), and lung surfactant mimic phospholipids (DPPC:DPPG=4:1 in molar ratio). The targeted dry powder for inhalation formulation for deep lung delivery with a built-in rationale of specifically interfering several disease factors of chronic infection diseases in deep lungs such as cystic fibrosis, pneumonia, chronic bronchitis, and etc. The dry powder aerosols consisting of selected chemical agents in one single formulation was generated by using spray drying from organic solution. The physicochemical properties of multi-component dry powder inhaler (DPI) formulation were characterized by a number of techniques. In addition, the in vitro aerosol dispersion performance, storage stability test, and in vitro drug release of selected spray-dried (SD) multi-component systems were conducted. The physicochemical study revealed that multi-component aerosol particles possessed essential particle properties suitable for deep lung delivery. In general, the multi-component particles (typically 0.5 to 2 µm) indicated that the designed SD aerosol particles could potentially penetrate deep lung regions (such as respiratory bronchiolar and alveolar regions) by sedimentation and diffusion, respectively. The essential particle properties including narrow size distribution, spherical particle and smooth surface morphologies, and low water content (or water vapor sorption) could potentially minimize interparticulate interactions. The study of in vitro aerosol dispersion performance showed that majority of SD multi-component aerosols exhibited low values (less than 5µm) of MMAD, high values (approximately above 30% up to 60.4%) of FPF, and high values (approximately above 90%) of ED, respectively. The storage stability study showed that azithromycin–incorporated multi-component aerosol particles stored at 11 and 40% RH with no partial crystallization were still suitable for deep lung delivery. Compared to SD pure azithromycin particles, the azithromycin-incorporated multi-component particles exhibited an enhanced initial release. The targeted microparticulate and nanoparticulate multi-component dry powder aerosol formulations with essential particle properties for deep lung pulmonary delivery were successfully produced by using spray drying from organic solution. The promising experimental data suggest the multi-component formulations could be further investigated in in vivo studies for the purpose of commercialization.