Recently, the portfolio of compounds approved for inhalation therapy has expanded rapidly for lung disease therapies. The rationale for this delivery approach includes a more targeted and localized delivery to the diseased site with reduced systemic exposure, potentially leading to decreased adverse side effects. We have proposed that brittle matrix powders prepared by thin film freezing (TFF) are a suitable platform for pulmonary drug delivery which can achieve high lung concentrations while limit the corresponding systemic levels associated with toxicity, and enhanced physicochemical and aerodynamic properties can be obtained by varying TFF processing parameters. In Chapter 2, the in vitro and in vivo performance of an amorphous formulation prepared by TFF and a crystalline micronized formulation produced by milling was compared for Tacrolimus (TAC). TFF processed matrix powders was capable of achieving deep lung delivery due to its low density, highly porous and brittle characteristics. When emitted from a Miat® monodose inhaler, TFF processed TAC formulations exhibited a fine particle fraction (FPF) of 83.3% and a mass median aerodynamic diameter (MMAD) of 2.26 µm. Single dose 24-h pharmacokinetic studies in rats demonstrated that the TAC formulation prepared by TFF exhibited higher pulmonary bioavailability with a prolonged retention time in the lung, possibly due to decreased clearance (e.g., macrophage phagocytosis), compared to the micronized TAC formulation. Additionally, TFF formulation generated a lower systemic TAC concentration with smaller variability than the micronized formulation following inhalation, potentially leading to reduced side effects related to the drug in systemic circulation. Chapter 3 investigated the impact of processing parameters in the TFF process on the physicochemical and aerodynamic properties of the resulting formulations. All of these enhanced powder properties resulted from higher freezing rate contributed to a better aerodynamic performance of the obtaining formulations. Moreover, a decreasing trend of FPF was observed for these TFF powders when the initial solid concentrations increased. The variation of the freezing rate and initial solid loading in the TFF process enabled the production of formulations with enhanced physicochemical properties and improved aerodynamic performance. / text

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The present thesis explores the relationship between occupational rhinitis and occupational asthma under the postulates of the "united airways disease" concept that refers to the multiple links observed between rhinitis and asthma. Accordingly, the main objective of this thesis is to demonstrate the concomitant expression of significant changes in nasal patency and bronchial calibre following exposure to occupational agents during specific inhalation challenges, complementing the assessment with the investigation of changes in markers of airways inflammation in nasal lavage. To achieve the objectives, we set up a protocol to diagnose occupational rhinitis and conducted a study from January 2005 to January 2007 at Hopital du Sacre-Coeur de Montreal in subjects undergoing investigation for occupational asthma. The reliability of the main research tools---acoustic rhinometry and nasal lavage---used to investigate occupational rhinitis was tested by analyzing the reproducibility of the methods. Both methods proved sufficiently reproducible to be included in our investigative protocol. The results presented in this thesis demonstrate a joint reaction of the nose and the lungs in a group of study subjects after performing specific inhalation challenge. This supports the concept of a "united airways disease" and its applicability to rhinitis and asthma of occupational origin. However, the results also show that although occupational rhinitis frequently coexists with occupational asthma it can also be present without occupational asthma. The assessment of upper airways inflammation in a subgroup of study subjects by the nasal lavage method allows us to observe significant changes in eosinophils counts after the challenge that correlates with the decrease in nasal patency observed in the same subjects.

Drug re-engineering is an effective method for engineering existing products in alternative dosage forms and with enhanced pharmacokinetics. Insulin for the management of diabetic symptoms is an ideal candidate for re-engineering. Current subcutaneous therapy results in low patient compliance and is ineffective in meeting the physiological need for post-prandial insulin. Implementation of dose titration for more efficient blood-glucose management is also inconvenient and uncomfortable. Inhaled insulin is presented as a superior alternative to current therapy. The lungs offer excellent access to the circulatory system. Aerosols suspended in inspired air may deposit on lung epithelia and be available for systemic absorption. To evade the defense mechanism of the human respiratory tract, particle sizes have traditionally been minimized to achieve necessary aerosol performance. Recent developments indicate that more efficient performance augmentation may also be achieved by decreasing the bulk density of powders and modifying surface characteristics. Light and fluffy powders with rough surfaces experience much higher drag forces within an airstream. The Atomized Rapid Injection for Solvent Extraction (ARISE) process is a unique precipitation platform devised by incorporating a rapid injection technique for energetic solution delivery into supercritical fluid (SCF) media to effect recovery of previously dissolved pharmaceutical compounds. The quasi-instantaneous delivery of solutions alleviates the drawbacks of the use of capillary nozzles or micro-orifices, gradual elution and mixing controlled precipitation kinetics in existing SCF precipitation techniques. Most importantly, the energetic release of solution into SCF media effects supersaturation over a much larger spatial volume and promotes the homogeneous precipitation of low bulk density powders. ARISE processed insulin powders displayed characteristics that were highly influenced by anti-solvent conditions and powders of different qualities were obtained as a function of anti-solvent pressures. At lower anti-solvent pressures, powders of narrow particle size distribution were achieved, an indication of homogeneous supersaturation levels within processing. Span, the index of size distribution was as low as 0.991. At higher anti-solvent pressures, supersaturation rates were increased while mixing efficiencies decreased, resulting in powders of wider size distribution, and powder bulk densities as low as 0.01 g/ml. Low bulk density insulin displayed in-vitro respirable fractions as high as 78%.

PhD / Electrostatics of aerosols for inhalation is a relatively new research area. Charge properties of these particles are largely unknown but electrostatic forces have been proposed to potentially influence lung deposition. Investigation on the relationship between formulation and aerosol charging is required to understand the fundamental mechanisms. A modified electrical low pressure impactor was employed to measure the particles generated from metered dose inhalers and dry powder inhalers. This equipment provides detailed size and charge information of the aerosols. The particles were sized by impaction onto thirteen stages. The net charges in twelve of the size fractions were detected and recorded by sensitive electrometers. The drug deposits were quantified by chemical assay. The aerosol charge profiles of commercial metered dose inhalers were product-dependent, which was due to differences in the drug, formulation, and valve stem material. The calculated number of elementary charges per drug particle of size ≤ 6.06 μm ranged from zero to several ten thousands. The high charge levels on particles may have a potential effect on the deposition of the aerosol particles in the lung when inhaled. New plastic spacers marketed for use with metered dose inhalers were found to possess high surface charges on the internal walls, which was successfully removed by detergent-coating. Detergent-coated spacer had higher drug output than the new ones due to the reduced electrostatic particle deposition inside the spacer. Particles delivered from spacers carried lower inherent charges than those directly from metered dose inhalers. Those with higher charges might be susceptible to electrostatic forces inside the spacers and were thus retained. The electrostatic low pressure impactor was further modified to disperse two commercial Tubuhaler® products at 60 L/min. The DPIs showed drug-specific responses to particle charging at different RHs. The difference in hygroscopicity of the drugs may play a major role. A dual mechanistic charging model was proposed to explain the charging behaviours. The charge levels on drug particles delivered from these inhalers were sufficiently high to potentially affect deposition in the airways when inhaled. Drug-free metered dose inhalers containing HFA-134a and 227 produced highly variable charge profiles but on average the puffs were negatively charged, which was thought to be due to the electronegative fluorine atoms in the HFA molecules. The charges of both HFAs shifted towards neutrality or positive polarity with increasing water content. The spiked water might have increased the electrical conductivity and/or decreased the electronegativity of the bulk propellant solution. The number of elementary charges per droplet decreased with decreasing droplet size. This trend was probably due to the redistribution of charges amongst small droplets following electrostatic fission of a bigger droplet when the Raleigh limit was reached.

Burn injuries represent a major cause of mortality and morbidity as well as a significant drain on limited resources, particularly in the developing world. Advances in resuscitation, critical care, protective ventilatory strategies, earlier complete debridement complemented by more aggressive treatment of burn wound sepsis have reduced the mortality of thermal injuries. There has also been a move to focus on education and prevention campaigns, which have borne fruit and resulted in some reduction in the incidence of burns in the paediatric population. Burn care, once a Cinderella specialty, has become a well focused multi-disciplinary specialty in its own right. Burn injury is dissimilar to many forms of trauma. In major burns, the initial trauma may be limited to the skin alone or skin and lungs, but all organ systems are rapidly involved as the physiological derangement becomes systemic. The burden of this multi-system insult is substantial. Globally, the World Health Organisation estimated that fire-associated burns alone directly resulted in over 320,000 deaths in 2002, and in the USA, approximately 1million children sustain burns each year. Australasian guidelines suggest that all adult burns with greater than 15% total body surface area (TBSA) and >10% TBSA burn in children will require fluid resuscitation and possibly critical care support at some point in their hospitalisation. Mortality in these patients with severe burns follows a bimodal pattern of early and late deaths. Causes of early death comprise refractory shock, inability to obtain a safe airway or provide adequate oxygenation, co-existent trauma, non-survivable carboxyhaemoglobin poisoning, and decisions that injuries are non-compatible with recovery, leading to therapy withdrawal. With improved resuscitation strategies, 95% of patients survive the early resuscitation phase. Late deaths are secondary to sepsis normally associated with wound infection and multiple organ failure. The morbidity associated with burn injury continues well after the acute hospital admission, frequently for up to several years post burn injury, as is witnessed by prolonged rise in basal metabolic rate and worsening scar tissue1, 2. It has been calculated that in children approximately 60% of the cost of burn care occurs post wound closure; that is, dealing with the disabling and disfiguring contractures associated with hypertrophic scar3, 4. Hence, research and new modalities are being aimed at reducing cost of treatment and improving quality of life for survivors of burn injury. Thus, this PhD aims to reflect the multidisciplinary nature of modern day burn care, with the inclusion of seven published papers and one book chapter covering prevention and education relevant to paediatric burns, treatment and minimisation of wound infection , and scar minimisation, along with the first study into the relevance of fetal wound healing post burn injury.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.