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.

Benzene and toluene are representative volatile organic compounds (VOCs) released during production, storage, and transportation associated with the oil and gas industry. Benzene and toluene are chemicals of concern because they are released in greater and possibly more biologically significant concentrations than other compounds. <p>Most studies of air pollution in high oil and gas activity areas have neglected to consider risks to top-level predators. Birds can be used as highly sensitive monitors of air quality. Since the avian respiratory tract is physiologically different from a rodent respiratory tract, effects of gases cannot be safely extrapolated from rodent studies. I hypothesized that benzene, being haematotoxic and immunotoxic, along with the neurological and possible endocrine disrupting effects of toluene would be more toxic in birds than in mammals. <p>After two summers of experimental exposure of wild and captive American kestrels to high (10ppm and 80ppm) or environmentally relevant (0.1ppm and 0.8ppm) levels of benzene and toluene, respectively, altered immune, haematopoeitic, behavioural, and endocrine responses characteristic in mammals, were evident in the kestrels.<p>There was a decreased cell mediated immune response as measured by delayed type hypersensitivity tests in all exposed birds (p = 0.028, 0.004). An increase in humoral immunity as compared to control individuals (p = 0.041, 0.031) was also apparent in both dose groups. Plasma retinol levels were decreased in 2005 and 2006 high dose individuals (p = 0.008, 0.048). <p>The majority of haematopoeitic effects involved the erythroid lineage in the bone marrow and the polychromatophilic erythrocytes systemically. There were no significantly adverse responses in the bone marrow with regards to the granuloid lineage but systemically there was a prominent eosinophilia (p = 0.045) and basophilia (p = 0.006) in low exposure groups. The loss of communication between polychromatophilic erythrocytes in the post-mitotic pool within the bone marrow and the peripheral blood was present in low and high exposure individuals compared to control birds (p = 0.013, 0.402, 0.974). The number of polychromatophils in the circulation of low dose group individuals was decreased compared to control birds (p = 0.029). This may be a function of toluenes inability to inhibit biotransformation enzymes at low concentrations leading to blood cell targeting by benzenes increased phenolic metabolite production. This theory is corroborated by the possible decreased benzene metabolism and increased toluene distribution manifesting as increased aggressive responses such as wing beating and vocalization time in the high dose group (p = 0.025, 0.086). <p>The work here has shown American kestrels are sensitive to the air contaminants, benzene and toluene. The present study illustrates the need for reference concentrations for airborne pollutants that are calculated based on data measuring sensitive endpoints specific for avian models. Future studies should evaluate immune, haematopoeitic, and behavioural endpoints, as well as develop more sensitive isoform specific enzyme activity assays to further determine the susceptibility of birds to inhaled toxicants.

I händelse av ett radioaktivt utsläpp är det viktigt att ha bra beredskap med skyddsåtgärder som bidrarmed det bästa skyddet för den utsatta delen av befolkningen. Direkt efter ett utsläpp utgör exponering viainandning det största problemet eftersom partiklar och gaser ännu inte hunnit deponerats på mark, imoln och så vidare. Byggnader bidrar med ett skydd mot inhalation eftersom luften utanför och inutibostaden byts ut relativt långsamt. Hur stor del av föroreningen som tar sig in till inomhusluften och hurlång tid detta tar är viktig information för att avgöra om befolkningen är tillräckligt skyddade inutibyggnader eller om evakuering bör ske. I detta arbete har kunskap från befintlig litteratur samtmodellering använts för att beskriva generella förhållanden med vilka en förorening kan ta sig in i och utur en byggnad. Differentialekvationer med huvudprocesser och ingående parametrar har studerats för attge en uppfattning om vilket skydd en byggnad kan ge mot inhalation av partiklar och gaser i ettradioaktivt moln. Olika typer av ventilationssystem med eller utan tillhörande partikelfilter diskuteras ochinhalationsdos för olika åldersklasser och aktivitetsnivåer undersöks.Genom att jämföra mängd förorening i luften utanför mot inuti en byggnad talar man om byggnadensskyddskoefficient. De tre huvudprocesser som styr transporten är ventilation, penetration samtdeponering. Ventilationen uppkommer av luftutbytet mellan inomhus‐ och utomhusluften. Ventilationenstyrs antingen mekaniskt eller naturligt. Penetrationen beskriver hur stor andel av partiklarna ellergaserna som tar sig in över byggnadens fasad och deponeringen hur partiklar och gaser tenderar attfastna på de ytor de passerar under transporten. Deponeringen sker även på samtliga ytor inutibyggnaden. Efter att ämnen deponerats kan de resuspendera och åter komma upp till luften vilketmöjliggör för inandning innan de åter kan deponera på tillgängliga ytor. Deponeringen ses som en sänkamedan resuspensionen fungerar som en källa för inomhuskoncentrationen.En av de faktorer som påverkar skyddskoefficienten till störst del är partikeldiametern eftersomdeponerings‐ och penetrationsprocessen är starkt storleksberoende. Stora och små partiklar deponeraslättare och kvar finns den så kallade mellanfraktionen, 0,2‐1 μm i diameter, som håller sig i luften längsttid. Gaser rör sig lätt in och ut ur byggnaden och hindras inte av partikelfilter. Däremot finns särskildafilter att installera som hindrar gaser att ta sig in, exempelvis kolfilter. Sönderfallshastigheten hos de olikaradionukliderna påverkar även skyddsfaktorn. Då ämnena sönderfaller minskar koncentrationen i luften,sönderfallet är då en sänka för koncentrationen inomhus. Ventilationshastigheten har en viss påverkan påskyddskoefficienten. En ökad ventilationshastighet leder till att koncentrationen inomhus kommer att gåmot penetrationsfaktorn. Detta gäller om ventilationshastigheten kan antas vara mycket större ändepositionshastigheten. Ventilationssystem utrustade med partikelfilter kan hålla en stor del avföroreningen utanför byggnaden. Partikelfiltren har olika effektivitet och klassificeras som grov‐, mediumsamtfinfilter. En hög filtereffektivitet har stor påverkan på skyddskoefficienten. Ett filter skall däremotses som en färskvara. De kräver underhåll och bör bytas ut i tid för att kunna fungera som de ska.Inhalationsdosen beror av partikelstorlek eftersom deponeringen som sker i luftvägarna fungerar påliknande sätt som i transporten in och ut ur byggnaden. Mellanfraktionen har tendens att tränga djupt nedi lungorna efter inandning. Effekten från inhalation beror på en individs ålder, storlek och fysisk aktivitet. / In case of a radioactive release, it is important to have good preparedness with the right actions to contribute the best protection for the vulnerable section of the population. Immediately after a release theexposure through inhalation will be the biggest problem, since particles and gases have not beendeposited on land, clouds and so on. Buildings contribute to protection against inhalation. The reason forthis is that the air outside and inside the dwelling is changed relatively slowly. How much of the pollutionthat enter the indoor air and how long time it takes is important information to determine if thepopulation is sufficiently protected inside buildings or if evacuation is needed. In this work knowledgefrom existing literature and modelling has been used to describe general conditions with which apollutant moves in and out of a building. Differential equations with main processes and parameters havebeen studied to give a estimation as to the protection a building can provide against exposure throughinhalation of particles and gases in a radioactive cloud. Different types of ventilation systems, with orwithout associated particle filter are discussed and inhalation dose for different age groups and activitylevels are examined.A buildings protection coefficient is defined by comparing the amount of pollution in the air outside withthe air inside a building. The three main processes that control the transport of the pollution in and outfrom a building are ventilation, penetration and deposition. Ventilation arises of air exchange betweenindoor and outdoor air. Ventilation is controlled either mechanically or naturally. Penetration describesthe proportion of the particles or gases that enter trough the buildings shell. Deposition of particles andgases accurse due to the fact that they tend to stick to the surfaces they pass in transit. The deposition alsooccurs on all surfaces inside the building. After the particles and gases have become deposited, they mayre‐suspend and come back up into the air permitting inhalation before they once more deposit onavailable surfaces. The deposit is seen as a sink while re‐suspension acts as a source for indoor airconcentration.One of the factors that have a large impact of a buildings protection factor is the particle diameter, due tothe deposition and penetration process strongly dependent on particles size. Large and small particlesdeposited easier and the remaining fraction, the midfraction (0.2 to 1 micron in diameter), remains. Thisfraction will stay in the air longer since the deposition process does not affect it strongly. Gases moveeasily in and out of the building and are not prevented by the particle filter. However, there are specialfilters to install that prevent gases to penetrate, such as carbon filters. The rate of decay of the variousradionuclides also affects the protection factor. When nuclides decay the concentration in the airdecreases, the decay is then a sink of the concentration indoors. Ventilation rate has a certain influence onprotection coefficient. An increased ventilation rate leads to the concentration inside approaching thepenetration factor; this is applied if the ventilation rate can be assumed to be much higher than thedeposit rate. Ventilation system equipped with a particle filter can keep a large part of the pollutantoutside the building. Particle filters have different efficiency and are classified as coarse, medium and finefilter. High filter efficiency has a major impact on the protection coefficient. For a filter to functionproperly it demands maintenance and should be replaced in time.Inhalation dose depends on the particle size, since the deposition process affected in respiratory functionis similar to the transport in and out of a building. The midfraction tends to penetrate deep into the lungsafter inhalation. The effect of inhalation is due to an individual's age, size, and physical activity.

Benzene and toluene are representative volatile organic compounds (VOCs) released during production, storage, and transportation associated with the oil and gas industry. Benzene and toluene are chemicals of concern because they are released in greater and possibly more biologically significant concentrations than other compounds. <p>Most studies of air pollution in high oil and gas activity areas have neglected to consider risks to top-level predators. Birds can be used as highly sensitive monitors of air quality. Since the avian respiratory tract is physiologically different from a rodent respiratory tract, effects of gases cannot be safely extrapolated from rodent studies. I hypothesized that benzene, being haematotoxic and immunotoxic, along with the neurological and possible endocrine disrupting effects of toluene would be more toxic in birds than in mammals. <p>After two summers of experimental exposure of wild and captive American kestrels to high (10ppm and 80ppm) or environmentally relevant (0.1ppm and 0.8ppm) levels of benzene and toluene, respectively, altered immune, haematopoeitic, behavioural, and endocrine responses characteristic in mammals, were evident in the kestrels.<p>There was a decreased cell mediated immune response as measured by delayed type hypersensitivity tests in all exposed birds (p = 0.028, 0.004). An increase in humoral immunity as compared to control individuals (p = 0.041, 0.031) was also apparent in both dose groups. Plasma retinol levels were decreased in 2005 and 2006 high dose individuals (p = 0.008, 0.048). <p>The majority of haematopoeitic effects involved the erythroid lineage in the bone marrow and the polychromatophilic erythrocytes systemically. There were no significantly adverse responses in the bone marrow with regards to the granuloid lineage but systemically there was a prominent eosinophilia (p = 0.045) and basophilia (p = 0.006) in low exposure groups. The loss of communication between polychromatophilic erythrocytes in the post-mitotic pool within the bone marrow and the peripheral blood was present in low and high exposure individuals compared to control birds (p = 0.013, 0.402, 0.974). The number of polychromatophils in the circulation of low dose group individuals was decreased compared to control birds (p = 0.029). This may be a function of toluenes inability to inhibit biotransformation enzymes at low concentrations leading to blood cell targeting by benzenes increased phenolic metabolite production. This theory is corroborated by the possible decreased benzene metabolism and increased toluene distribution manifesting as increased aggressive responses such as wing beating and vocalization time in the high dose group (p = 0.025, 0.086). <p>The work here has shown American kestrels are sensitive to the air contaminants, benzene and toluene. The present study illustrates the need for reference concentrations for airborne pollutants that are calculated based on data measuring sensitive endpoints specific for avian models. Future studies should evaluate immune, haematopoeitic, and behavioural endpoints, as well as develop more sensitive isoform specific enzyme activity assays to further determine the susceptibility of birds to inhaled toxicants.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 126-143).

Thesis--University of Oklahoma. / Bibliography: leaves 137-141.

The purpose of this study was to characterize and evaluate the performance of a whole-body human exposure chamber for controlled test atmospheres of gases and particulates. The chamber was constructed from Plexiglass, has a volume of 75 ft 3, operated at a flowrate of 33.8 CFM, and both the makeup and exhaust air are HEPA filtered. Fly ash dust was generated using a Wright Dust Feeder. An elutriator was used to eliminate particles larger 8 μm aerodynamic diameter from the airstream. A direct reading instrument, the Rupprecht and Patashnick PM-10 TEOM, was used for determination of particle concentration. Particle size distributions were determined by a QCM cascade impactor. Data from gravimetric analysis were used to test for the evenness of dust concentrations in the chamber. CO2 is used as a representative gas and its concentration was measured using the Metrosonics aq-5000. Total dust concentrations as measured by the TEOM, in μg/m 3, at 0.2, 0.4, 0.6 and 1.6 RPMs of the Wright Dust Feeder, were 110 + 2.8, 173 + 8.5, 398 + 20 and 550 + 17, respectively. For these RPMs, particle size distributions were associated with a MMD of 1.27 μm and a GSD of 2.35, a MMD of 1.39 and a GSD of 2.22, a MMD of 1.46 and a GSD of 2.08, a MMD of 1.15 and a GSD of 2.2, respectively. Total dust concentrations as measured by gravimetric analysis, in μg/m3 for the respirable fraction. Dust concentrations measured at different points within the chamber showed uniform distribution with a variability less than 10%. Similarly, the particle size distributions were found to be consistent across the different RPMs settings. Regarding carbon dioxide, its concentration was straightforward and the measured and theoretical maximum concentration levels were in agreement. The performance of this whole-body human exposure chamber has been characterized and evaluated for low levels of particles and gases and now it is a valuable research tool for inhalation challenge studies.

p-Dichlorobenzene (p-DCB) and naphthalene are compounds classified as Group C carcinogens according to the USEPA. Sources of p-DCB and naphthalene include moth repellents and deodorizers typically used in closets, garment bags, and toilet bowls found in pure form. In this study, laboratory, closet, and garment bag experiments were used to determine emission rates of p-DCB and naphthalene from consumer products (closet air freshener, toilet bowl deodorizer, and moth repellent). Emission rates varied considerably between products that contain p-DCB, primarily due to product packaging, and were generally suppressed when the product was used in a closed closet or garments bag, relative to products placed in well-ventilated chambers. Experimental mass emission rates were used in conjunction with a well-mixed reactor model to predict indoor p-DCB and naphthalene concentrations for a range of reasonable residential scenarios. Results suggest that exposures under worst-case scenarios could lead to excess lifetime cancer risks of greater than 20,000 in a million (2%) for those who use consumer products that are pure p-DCB, a risk that dwarfs any reported environmental cancer risks over large segments of the US population. Since such products are typically used where clothing is kept, significant chemical adsorption onto clothing is possible following sublimation from the solid product. Chamber experiments were used to determine the amount of p-DCB and naphthalene mass that adsorbs onto selected clothing materials made of cotton, polyester, or wool. Cloth specimens were kept inside a chamber through which an air stream containing p-DCB or naphthalene was passed for one month. After this time, p-DCB or naphthalene were chemically extracted from the cloth specimens. Polyester was determined to be the most adsorbent material, while cotton was the least adsorbent for each chemical. Equilibrium partition coefficients of 0.01 m³/g for p-DCB and 0.02 m³/g for naphthalene were determined experimentally for wool. Desorption rates were determined in both laboratory chambers and a closet in a test house. Results suggest prolonged persistence of p-DCB and naphthalene on polyester and wool, e.g., half-lives of 12 to 20 days after a moth repellent is removed from the clothes storage environment. An exposure scenario was also carried out to compare the inhalation and dermal exposure risks associated with contaminated clothing. / text

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