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Novel Dry Powder Inhalation System Based on Dispersion of Lyophilisates
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1 Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München Novel Dry Powder Inhalation System Based on Dispersion of Lyophilisates Sarah Christina Claus aus Groß-Gerau 2012
2 ERKLÄRUNG Diese Dissertation wurde im Sinne von 7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Wolfgang Frieß betreut. EIDESSTATTLICHE VERSICHERUNG Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, am Sarah Claus Dissertation eingereicht am Gutachter: Prof. Dr. Wolfgang Frieß 2. Gutachter: Prof. Dr. Gerhard Winter Mündliche Prüfung am
3 ACKNOWLEDGMENTS This thesis was prepared at the Department of Pharmacy, Pharmaceutical Technology and Biopharmaceutics at the Ludwig-Maximilians-University (LMU) in Munich in cooperation with the Respiratory Drug Delivery Unit of Boehringer Ingelheim Pharma GmbH & Co. KG (BI) in Ingelheim. Foremost, I would like to express my gratitude to my supervisor, Prof. Dr. Wolfgang Frieß for the possibility to join his research group and particularly for his valuable scientific support and enthusiastic guidance over the last years. Furthermore, I am thankful for the great opportunities to present my work at numerous international conferences. I also very much appreciated his personal advice and the creation of a pleasant and creative working atmosphere in the group. I also would like to thank the leader of the chair, Prof. Dr. Gerhard Winter, for creating excellent working conditions and for supporting numerous social activities. Thank you also very much for taking over the role of co-referee of this work. Boehringer Ingelheim Pharma GmbH &Co. KG is gratefully acknowledged for scientific, experimental, and financial support. Special thanks go to Dr. Tilo Schönbrodt for the initiation of the project and for giving me the opportunity to conduct this study at the LMU in cooperation with BI. I would also like to thank him for his guidance and valuable scientific support during the first year. Special thanks also go to Dr. Claudius Weiler for taking over the supervision of this project at BI, for his enthusiastic guidance, and for all the scientific input. Many thanks are also expressed to Dr. Jörg Schiewe, Dr. Markus Wolkenhauer and Dr. Herbert Wachtel for their support and the interesting scientific discussions we had. I would also like to express special thanks to Marion Dörner, Ronald Frieß, Benjamin Welter, and Stefan Walter for their support with experiments in the lab, Holger Holakovsky and Gilbert Wuttke for the possibility to perform the high speed camera recordings, Dr. Herbert Wachtel and Andree Jung for the support to do the Aerosizer measurements, as well as Dr. Karl Wagner and Birgit Schwarz for the support with the compression analysis. From the Department of Chemistry of the LMU I want to thank Christian Minke for his support with SEM analysis and Wolfgang Wünschheim for the access to the x-ray diffractometer.
4 I want to thank Prof. Dr. Franz Paintner, Prof. Dr. Stefan Zahler, Prof. Dr. Christian Wahl- Schott, and Prof. Dr. Ernst Wagner for kindly serving as a member for my examination board. My thanks are also extended to the assisting students Florian Prändl, Elisabeth Berto, Felicitas Keller, Alexandra Pickel, Katharina Hümpfner and Annette Starke for the good job they did during their internships. I want to thank all my PhD colleagues from the research groups of Prof. Frieß and Prof. Winter for their warm welcome, their contribution to the great working atmosphere, the inspiring scientific discussions, the nice coffee breaks and the various leisure-time activities. Particularly I want to mention Julia, Eva, Kerstin, Winnie, Tim, Philipp, Katja, and Lars. Thank you for your support, your friendship, and for the good time we spent together in- and outside the lab. I want to express special thanks to Julia for scientific input and all the valuable discussions about freeze-drying. Special thanks go also to my lab and office mates Eva, Kerstin, Imke, Katja and Miriam for the nice atmosphere and the great time we spent together. I want to thank my parents Nannette and Günter, my parents-in-law Waltraud and Martin and my brother Nicolai with Katherine for their encouragement and great support in all the years. Finally, I would like to thank Tobias for proofreading of this work, all his support and patience. Heartfelt thanks for your love.
5 For my parents and Tobias
6 TABLE OF CONTENTS Chapter 1 General Introduction and Objective of the Thesis General Introduction Why pulmonary drug delivery? Devices for pulmonary drug delivery New powder formulation methods Engineered particles High dose DPI formulations on the market and in research and development Adverse effects of high dosed powder pulmonary delivery Conclusion Objective of the Thesis References Chapter 2 The Test System Introduction Materials and Methods Materials Design of experiments (DoE) Formulation preparation in glass vials Formulation preparation in polyethylene capsules Andersen cascade impactor (ACI) analysis Simulation of the air flow through the device High speed camera recordings Particle size distribution (PSD) analysis ED analysis of lactose powders of different particle size Mechanical testing Results and Discussion Construction of an output test system Influence of vial and stopper geometry on fine particle output Influence of mouthpiece with sheath air Simulation of the air flow in the vial The aerosolization behavior of the lyophilisate in the vial Influence of the particle size on the output Evaluation of lyophilisate dispersion in the passive Handihaler Summary and Conclusion I
7 5 References Chapter 3 Evaluation of the Performance of the Test System Introduction Materials and Methods Materials Formulation preparation Microscopy X-Ray diffractometry (XRD) Residual moisture content analysis Differential scanning calorimetry (DSC) Particle size distribution (PSD) analysis Laser diffraction (LD) measurements Time of flight (TOF) measurements Andersen cascade impactor (ACI) analysis Tap density measurement Results and Discussion Physicochemical characterization of excipient formulations PSD of different excipient formulations Summary and Conclusion References Chapter 4 Optimization of the FPD by Increase of the Solution Concentration and the Fill Volume Introduction Materials and Methods Materials Formulation preparation FPF analysis Mechanical testing High speed camera recording Results and Discussion Optimization of the FPD of valine lyophilisates Optimization of the FPD of cromolyn sodium lyophilisates and comparison to a high dose market product Summary and Conclusion References II
8 Chapter 5 Optimization of the FPF of a Lyophilized Lysozyme Formulation for Dry Powder Inhalation Introduction Materials and Methods Materials Formulation preparation X-Ray diffractometry (XRD) Device Fine particle fraction (FPF) analysis Mechanical testing High speed camera recording Microscopy and scanning electron microscopy (SEM) Stability testing Residual moisture content analysis Results Optimization of the FPF by addition of excipients Storage stability of 12 mg/ml lysozyme-4 mg/ml phenylalanine-formulation Variation of the FPF by variation of the freezing method Discussion Optimization of the FPF by addition of excipients Storage stability of 12 mg/ml lysozyme-4 mg/ml phenylalanine-formulation Variation of the FPF by variation of the freezing method Summary and Conclusion References Chapter 6 Effect of Variation of the Lyophilisate Morphology on the Fine Particle Fraction Introduction Materials and Methods Materials Formulation preparation (aqueous solutions) Formulation preparation (TBA/water co-solvent systems) X-Ray diffractometry (XRD) Mechanical testing of lyophilisates Device Fine particle fraction (FPF) analysis Microscopy High speed camera recording III
9 2.10 Mechanical property testing of freeze-dried substances via compaction Results Variation of the freezing process Microscopic appearance Mechanical characterization of the lyophilisates by indentation Aerosolization characteristics Aerosolization performance Particle characteristics Changing the ice crystal habitus using TBA as co-solvent Analysis of the material properties by compression studies Discussion Variation of the freezing process Changing the ice crystal habitus using TBA as co-solvent Analysis of the material properties by compression studies Summary and Conclusion References Chapter 7 Storage Stability of Lyophilized Formulations for Dry Powder Inhalation Introduction Materials and Methods Materials Formulation preparation Storage Moisture content analysis Moisture sorption analysis Mechanical testing X-Ray diffractometry (XRD) Fine particle fraction (FPF) analysis Results and Discussion Three-month stability at 25 C/60% RH and 40 C/75% RH Stress test: open storage at RT/30% RH and RT/50% RH Summary and Conclusion References Chapter 8 Summary of the Thesis List of Abbreviations Presentations and Publications Associated with this Work Curriculum Vitae IV
10 Chapter 1 General Introduction and Objective of the Thesis Abstract In the last decades, dry powder inhalation has become a very attractive option for pulmonary drug delivery to treat lung diseases like cystic fibroses and lung infections. In contrast to the traditional pulmonary application of drugs for asthma and chronic obstructive pulmonary disease, these therapies require higher lung doses to be administered. The developments and improvements towards high dose powder pulmonary drug delivery are summarized and discussed in this chapter. These include the invention and improvement of novel inhaler devices as well as the further development of formulation principles and new powder engineering methods. The implementation of these strategies is subsequently described for some prototypes and formulations in research and development stage as well as for already marketed dry powder products. Finally, possible adverse effects which can occur after inhalation of high powder doses are shortly addressed. 1
11 Chapter 1 1 GENERAL INTRODUCTION 1.1 WHY PULMONARY DRUG DELIVERY? The main benefit of pulmonary drug administration is the delivery directly to the location of the disease while minimizing systemic exposure and toxicity [1]. Pulmonary delivery is characterized by rapid clinical response and allows to bypass therapeutic barriers such as poor gastrointestinal absorption and first-pass metabolism in the liver [2]. It can achieve a similar or superior therapeutic effect at a fraction of the systemic dose. For example, an oral dose of 2 4 mg salbutamol is therapeutically equivalent to µg by inhalation [2]. This is particularly important when considering aminoglycoside antibiotics for the treatment of Pseudomonas aeruginosa infections of the lung. Only low sputum aminoglycoside concentrations are achieved by administration of relatively high intravenous doses which carry the potential for systemic toxicity whereas high sputum concentrations can be achieved by inhalation without the risk of systemic toxicity [3]. For the treatment of lung diseases like asthma and chronic obstructive pulmonary disease (COPD) inhaled medications have been available for many years. Devices and formulations were designed for the administration of relatively low doses ranging from 6 to 500 µg [4]. In recent years, the treatment of other diseases like cystic fibroses and lung infections, as well as systemic diseases by pulmonary administration, became more attractive. However, these therapies in general require higher doses to be effectively administered to the lung. 1.2 DEVICES FOR PULMONARY DRUG DELIVERY Systems for pulmonary delivery include pressurized metered dose inhalers (pmdi), soft mist inhalers, nebulizer and dry powder inhalers (DPI). With respect to delivered dose, pmdis and the Respimat soft mist inhaler were designed for the delivery of highly potent drugs for the treatment of asthma and COPD but face several factors limiting high dose delivery. Due to a poor delivery efficiency (mean lung deposition of 12%), a small metering valve of µl [5], and limited increase in concentration [6] only small delivered doses of less than a milligram per puff can be achieved with pmdis [7]. The Respimat soft mist inhaler improved delivery efficiency to about 40% but high dose delivery is still limited by a small metering chamber of only 15 µl [8]. Thus, pulmonary delivery of high drug doses has been realized by nebulization of liquid formulations. This way of administration has some drawbacks such as restricted portability of jet and ultrasonic nebulizers due to the required 2
12 General Introduction and Objective of the Thesis power source as well as a noisy compressor for jet nebulizers. These drawbacks were improved for portable battery-powered vibrating mesh nebulizers. The administration is nevertheless time-consuming and regular cleaning and disinfection of the systems are required [9]. Particularly for cystic fibrosis (CF) patients, applying several aerosol therapies, the time burden is immense. It may take up to three hours per day for administration of drugs and then to clean and sanitize the aerosol equipment [7]. DPIs have the capacity to deliver higher payloads of drug to the lung. The first DPI (Aerohaler) was used in 1964 for the inhalation of 100,000 units of crystalline penicillin G sodium dust (approximately 60 mg) three times a day to treat patients with various infections of the respiratory tract [10]. In 1971 the Spinhaler was developed [11] and approved for the delivery of 20 mg of the anti-asthmatic drug cromolyn sodium [12]. However, early DPI devices featured poor delivery efficiencies (only 4 to 17% lung delivery for cromolyn sodium) and the dosing performance depends on the patient s inspiratory flow rate [13, 14]. In order to be effectively delivered to the alveolar region, particles must have an aerodynamic size between 1 and 5 µm [2]. Particles in this size range are extremely adhesive and cohesive. To improve powder fluidization and aid in de-aggregation, the micronized drug is either formulated with controlled agglomeration (soft pellets) or, most often, blended with larger carrier particles [15] in a drug-carrier ratio of usually 1:67.5 [16, 17]. The high percentage of carrier particles and the poor delivery efficiency limit the maximum lung dose which can be delivered in one actuation to just a few milligrams [6]. For administration of an appropriate lung dose of the antiviral drug zanamivir, for example, the patient needs to inhale two blisters containing 5 mg zanamivir formulated with 20 mg lactose-monohydrate twice a day [18]. Additionally, the large variations in lung deposition which depend on the inspiratory flow rate restrict the standard blending technology to drugs with a relatively large therapeutic index [19]. To overcome these limitations, DPIs experienced continuous further development. A specific de-agglomeration zone was introduced for enhanced fine drug particle separation by turbulences and multi-dose DPIs were designed [4]. The Novolizer and the AirMax TM device use tangential air flow which forms a cyclone in the device for optimized powder dispersion [20]. This approach improves lung delivery [21] but still shows variable performance at different flow rates [22, 23]. In contrast, drug delivery of the Taifun device, which incorporates a vortex chamber, is relatively independent of the inhalation flow [24]. Constant drug deposition at different flow rates is also shown for the Turbospin device where the inspiratory air is drawn through aerodynamically designed slits of the capsule chamber, putting it in a vortical motion. This causes shaking and twisting of the capsule for efficient 3
13 Chapter 1 powder release [25, 26]. DPIs which include an active mechanism for powder dispersion are less dependent on the patient s inspiratory flow, which is particularly important when considering systemic drug delivery. The Exubera and the Aspirair TM device are aimed for systemic delivery and use compressed air for powder aerosolization [27-29]. Nevertheless, all of the devices described above are designed for the delivery of small doses. DPI with drugs like anticholinergics, beta-2-agonists or glucocorticoids to treat asthma and COPD contain between 6 and 500 µg drug per dose [4]. An apomorphine hydrochloride formulation at µg for the treatment of male erectile dysfunction was recently developed using the Aspirair TM device [29]. The Exubera device was designed for the delivery of 1 or 3 mg of a dry powder insulin formulation to treat diabetes [27, 28]. In spite of still existing limitations for the delivery of larger doses, Crowther-Labiris et al. [3] delivered a lactose-blended micronized gentamicin dry powder formulation from the Clickhaler device (nominal dose of 160 mg gentamicin) to ten chronically Pseudomonas aeruginosa infected patients, which had to take 32 inhalations to achieve a cumulative lung dose of 60 mg gentamicin. A new device, designed for the delivery of high powder doses, is the Twincer for the application of antibiotics and sugar glass formulations containing, for example, therapeutic proteins. De Boer et al. [30] demonstrated that powder doses up to 25 mg of pure drug can effectively be de-agglomerated, which possibly could be further optimized to a dose of 50 mg. For 8 mg colistin sulfomethate, fine particle fractions between 40 and 60% were achieved, depending on the size of the classifier chamber. The Twincer was designed as a low cost disposable inhaler, which makes it also interesting for medications that have to be given only once (e.g. vaccines) [30]. Another interesting novel dry powder inhaler for the delivery of high dose ( mg) cohesive powders was described by Young et al. [31, 32]. The inhaler aerosolizes powder by using pressurized canisters filled with nitrogen gas at a pressure of 6-14 bar. An FPF between approximately 20 and 40% related to delivered dose could be achieved with a loading dose of 120 mg. A similar approach by using a standard propellant canister is described by Winkler et al. [33]. Up to 16 mg fine particle dose is reported in combination with that device. Recently the Novartis Podhaler (T-326 Inhaler) was approved, which evolved from the Turbospin device, to address the needs of high-payload delivery of engineered tobramycin particles of around 50 mg. Similar to the Turbospin device, the vortical air flow causes the capsule to spin while powder is shaken out of two pierced holes and aerosolized [34]. In vitro particle deposition were found to be largely independent of the inhalation maneuver [35]. 4
14 General Introduction and Objective of the Thesis 1.3 NEW POWDER FORMULATION METHODS New powder formulation methods are equally important as sophisticated devices for an efficient delivery of high dose DPI products. Owing to their small size, micronsized particles are extremely adhesive and cohesive. To enhance powder flowability and dispersibility, the main formulation method is blending with large (30-90 µm) lactose carrier particles [17]. For these formulations two oppositional requirements must be fulfilled. On the one hand, adhesion between carrier and drug must be sufficient for the blend to be stable enough to allow handling like filling. On the other hand, it needs to be weak enough to enable the release of drug after inhalation when the carrier particles retain in the inhaler device or deposit in the oropharynx due to their large size. Drug detachment from the carrier during aerosolization is therefore crucial for efficient lung delivery [36]. To prevent incomplete deagglomeration and improve lung delivery, different methods have been applied to weaken the drug adhesion including smoothing the carrier surface [37], reducing the particle size of the carrier [38], and using ternary mixtures with fines of e.g. lactose or hydrophobic components like magnesium stearate or amino acids [37, 39, 40]. Surface roughness of the carrier particles (in contrast to the surface roughness of small inhalable particles) may introduce asperities which could entrap drug particles and may resist its detachment from the carrier during inhalation [41, 42]. Two mechanisms by which fines improve de-aggregation are suggested because the aerosolization performance of the drug was shown to be both affected and unaffected by the blending order [43]. First, fines could prevent the drug particles from adhering to the strongest binding sites on the carrier [39] and, second, fine excipient and drug particles form agglomerates which are more easily dispersed and de-aggregated during aerosolization [44]. A second strategy to overcome uncontrolled agglomeration of micronsized particles is the controlled agglomeration into soft aggregates by spheronization. These soft pellets exhibit large particle sizes, which provide the required flow properties for accurate dosing and are hard enough to be handled and loaded into the inhaler but still easily break apart into primary particles during inhalation [45]. Nevertheless, the variability of dose emissions from such DPI systems has been found to be relatively high, with a total relative standard deviation of more than 15% of the average emitted dose [46]. Additionally, the formed soft aggregates can harden on the surface when exposed to moisture, which influences the dosing characteristics and the ability to disaggregate into primary particles at inhalation. Therefore, the inhaler (Turbohaler ) contains a desiccant, which is stored in the operating unit of the inhaler [45]. 5
15 Chapter ENGINEERED PARTICLES Drug delivery to the lung can also be improved by particle engineering, which aims at the production of drug particles of optimal size, morphology and structure [42]. At best, these engineered formulations can overcome the need of carrier blends to enhance powder flowability and thus reduce the need for large amounts of excipient in the formulation. Direct controlled crystallization, for example, enables the production of uniform crystal drug particles with better physical stability due to a lower amorphous content compared to micronized material [42]. Through the use of an antisolvent precipitation technique with growth-retarding stabilizers like hydroxypropylmethylcellulose, characteristic particle morphologies depending on crystalline polymorphs can be achieved [47]. Elongated particles show improved lung delivery because the aerodynamic diameter of a fiber is mainly determined by its width rather than by its length [48]. Ikegami et al. [49] performed solidstate transformation of a steroid from one polymorph to another and demonstrated an eightfold increase of the FPF for the needle-like particles of the β-form compared to the platelike α-form. Nevertheless, particle size control remains a big challenge because most molecules tend to form relatively large crystals [42]. Several particle engineering technologies with the supercritical fluid carbon dioxide have been applied for pulmonary powder production. Particles form either as the result of rapid expansion of the supercritical fluid in which the components are dissolved or when the supercritical fluid acts as an antisolvent and causes precipitation from a solution [50]. It has been shown that powders produced by supercritical antisolvent precipitation typically exhibit a platelet particle morphology with lower bulk density and smaller cohesive-adhesive interactions compared to micronized powder, which enhances its dispersibility at low airflow rates [42]. Additionally, the controlled production of different polymorphic forms of high purity has been demonstrated [51]. The rapid expansion technique is only applicable if the compound has a significant solubility in the supercritical fluid and, if so, it is the technique of choice because of its simple, direct, solvent-free and continuous production of respiratory powder [42]. Spray drying is a well-established method in food and pharmaceutical industries with increasing popularity due to its applicability to formulate biopharmaceuticals [50, 52]. It is one of the most sophisticated drying techniques and offers many possibilities for modification and particle engineering. The product characteristics can be modified by process and formulation parameters like nozzle type and nozzle parameters, feed concentration and rate, 6
16 General Introduction and Objective of the Thesis solvent, drying gas flow rate, temperature and humidity as well as excipients used [53, 54]. Spray drying is also applicable for many liquid systems like solutions, suspensions, as well as emulsions and it offers the possibility of mixing fluids immediately prior to or simultaneously with the atomization process [54]. Beside conventional spherical particles, spray drying permits also the controlled production of particles of different morphology. Corrugated particles can be attained, for example, by changing the spray drying process conditions [55-57], by employing polymeric excipients like dextran to increase the solution viscosity [58] or by adding low soluble components like leucine and trileucine [59-61]. These particles have a lower density and thus a larger geometrical size which improves powder dispersibility due to higher drag forces in the air stream. In addition, cohesive forces are reduced due to a smaller radius of curvature in the contact zone [58]. Spray drying has also been used in various methods for the preparation of porous particles. Vanbever et al. [62] prepared large porous particles by spray drying of a combination of water soluble (e.g. lactose) and water insoluble materials (e.g. dipalmitoylphosphatidylcholine) in an 87% ethanolic solution at a relatively low solid content (0.1% w/v). The particles had mean geometric diameters between 3 and 15 µm but very small densities (tap density of g/cm 3 ), resulting in high emitted doses and respirable fractions. Another technique for the production of porous particles by spray drying is the PulmoSphere technology [63]. PulmoSphere particles are manufactured by an emulsion-based spray drying process. The drug is incorporated in an oil-in-water emulsion, which is composed of perfluorooctyl bromide and water and stabilized by the phospholipid distearoylphosphatidylcholine (DSPC), an endogenous pulmonary surfactant. During spray drying the drug diffuses to the center of the atomized droplet whereas the excipients form a shell at the surface. The volatile perflubron evaporates after further drying, leaving behind pores in the particle which form a sponge-like morphology. The particles have geometric sizes between 1 and 5 µm and are spherical in shape with a porous surface. This decreases the contact area between particles and leads to less particle agglomeration. Additionally, the accumulated DSPC at the surface lowers the surface energy, which further aids in decreasing interparticle cohesive forces. Consequently, PulmoSphere particles have good flow and dispersing properties [63], allowing processing and aerosolization without the need to blend with carriers [64]. Spray freeze-drying is a related method and a useful process for drying thermosensitive molecules like proteins. An atomized liquid is frozen in liquid nitrogen and freeze-dried for the production of micronsized porous powder particles. Nevertheless, the atomization step and the extremely rapid freezing of droplets impose substantial stresses on proteins distinct 7
17 Chapter 1 from those stresses created by conventional lyophilization [65]. Compared to spray drying the technique allows higher production yield and superior aerosol performance because of the particles porosity. On the downside, the process is more complex, time-consuming, and cost intensive [66]. Additionally, the fast freezing of small droplets produce very fine microstructures after drying resulting in friable powders [65, 67]. Particles for sustained release can be formed from liquid dispersed systems via emulsionbased methods using biodegradable polymers like poly(lactide-co-glycolide) (PLGA) for microencapsulation of the drug. Traditionally, these methods have been applied for the preparation of injectables [42]. Numerous examples of sustained release microspheres for pulmonary delivery are published, which contain drugs like isoproterenol for sustained bronchodilation [68] or isoniazid/rifampicin for treatment of pulmonary tuberculosis [69]. Porous particles with increased delivery efficiency have also been prepared from liquid dispersed systems using PLGA. Applying this method, Edwards et al. [70] demonstrated improved bioavailability of large porous insulin particles which were about seven times bigger than small nonporous insulin particles. The positive effect was explained by two factors: first, the increased particle size results in decreased tendency to aggregate and therefore more efficient aerosolization; second, large particles may escape from phagocytosis by alveolar macrophages [70, 71]. However, it is important to note, that polylactide has been shown to cause adverse immunological responses, which result in a significant damage of the lung after 24 h [72]. Another particle engineering method for pulmonary drug delivery is a drug carrier technology developed by MannKind Biopharmaceuticals, which captures and stabilizes peptides or proteins in small precipitated particles. These light microspheres (Technospheres ) with a rough surface are formed by the ph-induced intermolecular self-assembly of 3,6-bis(Nfumaryl-N-(n-butyl)amino)-2,5-diketopiperazine. During the precipitation process, peptides and proteins which are present in the solution are microencapsulated. The precipitates are freeze-dried and become a light powder [73]. Efficacy, reliability and short-term tolerability of this drug delivery system has been demonstrated in clinical studies for parathyroid hormone [74] and insulin [75]. 8
18 General Introduction and Objective of the Thesis 1.5 HIGH DOSE DPI FORMULATIONS ON THE MARKET AND IN RESEARCH AND DEVELOPMENT As the first high dose antibiotic dry powder formulation (european medicines agency (EMA) approval in July 2011), tobramycin PulmoSphere reached the market with the TOBI Podhaler (Novartis AG, Basel, Switzerland). The total amount of 112 mg of tobramycin formulation is administered by the inhalation of four capsules twice a day [76]. This portable passive delivery system demonstrates the same delivery efficiency as the jet nebulized 300 mg tobramycin solution for inhalation (TOBI Pari-LC Plus), which is powered by an air compressor and requires an administration time of 15 to 20 min [77] as well as additional cleaning time. Fine particle dose (FPD) values of the market product are not published, however, an earlier study with 25 mg/capsule demonstrated a mean lung deposition of 34% [78]. In February 2012, the EMA approved Colobreath (Forest Laboratories, Inc.). It is a dry powder formulation of colistimethate sodium administered using the Turbospin DPI. One capsule contains 125 mg colistimethate to be inhaled twice a day [79]. The lung delivery efficiency is not published. Several other high dose dry powder antibiotic formulations are in development. A ciprofloxacin PulmoSphere formulation (Cipro Inhale) is currently in phase II clinical trial [80]. For a study in healthy volunteers, capsules were filled with 50 mg powder containing an active dose corresponding to 32.5 mg ciprofloxacin betain and was administered via the T-326 Nektar Inhaler (Podhaler ) [81]. The achieved FPD is not published. Positive results were recently demonstrated in a phase I clinical study for AeroVanc (Savara Inc.), a dry powder formulation of vancomycin. It is the first inhaled antibiotic being developed for the treatment of respiratory methicillin-resistant Staphylococcus aureus (MRSA) infection in patients with CF. The dose-escalating study included doses between 16 and 80 mg and examined the tolerability, safety, and pharmacokinetics of AeroVanc in non- MRSA infected CF patients in comparison to a 250 mg dose of vancomycin administered intravenously [82]. The lung delivery efficiency is not published, however, sputum concentrations of vancomycin known to effectively kill MRSA could be demonstrated [83]. Aquino et al. developed a dry powder formulation of gentamicin by particle engineering via spray drying. The formulation including 15% (w/w) leucine was spray dried from a water/co- 9
19 Chapter 1 solvent system containing 30% (w/v) isopropyl alcohol and resulted in corrugated particles. A capsule charged with 120 mg powder introduced into the Turbospin emitted almost the whole dose and achieved an in vitro FPD of 56 mg [59]. Not only antibiotics exist among high dosed dry powder formulations for inhalation. Mannitol (Aridol, Pharmaxis Pharmaceuticals Limited), for example, is used in asthma diagnosis to identify persons with bronchial hyper-responsiveness [84]. For the bronchial provocation test patients are supposed to inhale the mannitol powder in increasing doses with the following protocol: 0 (empty capsule acting as a placebo), 5, 10, 20, 40, 80, 160, 160, and 160 mg mannitol whereby the 80-, and 160-mg doses are given in multiples of 40-mg capsules [85]. Another inhalative mannitol product is Bronchitol, which was recently approved by the EMA for the treatment of CF patients aged 18 years and above for the improvement of lung function. A dose of 400 mg spray-dried mannitol is administered twice a day by inhalation of 10 capsules using the Cyclohaler. The osmotic active mannitol helps in rehydration and clearance of the tenacious mucus [86, 87]. Achieved FPDs are not published. Several other drugs for high dose pulmonary administration are considered in research. Among them are, for example, low molecular weight heparin [88], lung surfactant [89] and an NK1 receptor antagonist [90]. 1.6 ADVERSE EFFECTS OF HIGH DOSED POWDER PULMONARY DELIVERY The inhalation of large powder doses is regarded critical compared to nebulized liquids because of potential induction of bronchoconstriction in hyper-responsive lungs (e.g. asthma patients). Dry powder mannitol has been shown to present an osmotic challenge to hyperresponsive lungs at high dose and is therefore used for asthma diagnosis [84, 91]. Nevertheless, in non-asthmatic patients, large amounts of inhaled powder can also provoke upper-airway irritation, coughing, and bronchospasm which were reported as primary adverse events in various clinical studies. For Colobreath these adverse effects normally diminish upon continued application or can be weakened by additional inhalation of β 2 -agonists [79]. Mannitol for inhalation in CF patients provoked cough during the first treatment but was overall well tolerated [87]. The inhalation of tobramycin dry powder formulation most commonly caused cough, followed by lung disorders (generally reported as a pulmonary or CF exacerbation) and pharyngolaryngeal pain (sore throat) but were considered as not serious. Both phase III studies demonstrated that tobramycin inhalation powder was well tolerated in CF patients [92, 93]. Crowther-Labiris et al. [3] reported in a comparative study of dry 10
20 General Introduction and Objective of the Thesis powder versus intravenous and nebulized gentamicin, that nebulization of gentamicin caused significantly more mouth and throat irritation, induced coughing, and an unpleasant taste compared to the dry powder inhalation. 1.7 CONCLUSION The growing interest in the pulmonary administration of larger powder doses triggered both, the invention of novel inhaler devices with enhanced efficiency and the development of improved inhalation formulations. Another goal was to minimize variations in the aerosolization and delivery performance and to reduce the dependency on the patient s inspiratory flow. New sophisticated systems demonstrated their capability to deliver significantly increased lung doses compared to the simple early devices. Active as well as some passive devices achieved also inspiratory flow-independent delivery. In particular, particle engineering to improve powder properties play a significant role in leading dry powder formulations towards efficient delivery of large powder quantities. The engineered PulmoSphere particles, for example, facilitated the development of the first marketed high dose antibiotic dry powder for pulmonary administration. Nevertheless, to achieve sufficiently high lung doses, every drug administration consists of multiple inhalations, which still leaves enough room for further improvement. The reported advances in particle engineering also opened the opportunity for the formulation and delivery of more complex and labile drugs like biopharmaceuticals. 11
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text: Wintertime, and the living is...freezing. As the rest of the country remains in cold mode, California is mild as always. Sunny skies and balmy breezes. So why not make a blue movie celebrating it and its juicy young men? Director Max Phillips has put together a fresh-faced cast of sun-tanned cuties for Buckshot's California Boys. Porn stars Marc Dylan and Adrian Long start the fun with an early morning duo. The muscle studs greet the day with wet kisses, which tend to awaken other body parts. Morning wood for breakfast never tasted so good! Hot 69 sucking ensues, and it isn't long before Long starts focusing on Dylan's tight bubble butt. "I want you to fuck me!" Marc moans. "Hard and deep." Done and done! Low and slow quickly builds to hard and fast. As Adrian drills his tight hole, Marc spews a white-hot load of jizz. Long uses a double-handed jack to shoot his own stream of cum across Dylan's lightly furred pecs. Let the day begin! Also starring Alex Andrews, Jessie Jordan, Steve Vex, Jay Roberts, Hayden Michaels and Cameron Marshall. For more information, visit COLTStudioGroup.com.

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60" S/s Pizza Prep Table Cooler 15.9 Cu.Ft
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Thanks Darren Schoen for the great training. I know that I really learned a lot, plus it was nice meeting with other local IT experts here in Portland. Now I'm planning on attending the next Portland area Spicecorps meeting which is being held on June 1st.
Also, Michael Black, if you read this, here is the script for enabling WMI that you wanted. :)
netsh advfirewall firewall set rule group ="windows management instrumentation (WMI)" new enable=Yes
Also remember that this is for your Windows 7 machines only, but it should take care of all of the firewall scan errors.
1 Reply
May 25, 2011 at 2:18 UTC
I agree with Steve that the training and meeting other local IT pros was good. The training helped me see a bit more of the features of Spiceworks and has gotten me over the reluctance to dive in.
Since I'm more willing to dive in I've taken a look at my inventory more closely and have discovered missing or only partially scanned Windows 7 computers. The script mentioned above is what I used to get them to show up in Spiceworks.
This discussion has been inactive for over a year.
You may get a better answer to your question by starting a new discussion.


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FLYING DUCK ORCHID Seeds
FLYING DUCK ORCHID Seeds (Caleana Major)
Price for Package of 5 seeds.
Caleana major, the flying duck orchid, is a small orchid found in eastern and southern Australia. This terrestrial plant features a remarkable flower, resembling a duck in flight. The flower is an attractant to insects, such as male sawflies which pollinate the flower in a process known as pseudocopulation. In
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United States
DJ in NYC. I play regular parties at Wythe Hotel, Tandem Bar, The Commodore, and other venues, as well as many private events. [email protected]
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Sauer Paul F Md provides pediatric plastic surgery in Birmingham, AL. A Pediatric Plastic Surgeon specializes in pediatrics, birth defect, cleft lip, webbed fingers, birthmarks, burns, reconstructive surgery and pediatric plastic surgery.
Please call Sauer Paul F Md at (205) 592-9928 to schedule an appointment in Birmingham, AL or to get more information.
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Sauer Paul F MD can be found at Montclair Rd 840. The following is offered: Doctors & Clinics. The entry is present with us since Sep 9, 2010 and was last updated on Nov 14, 2013. In Birmingham there are 525 other Doctors & Clinics. An overview can be found here.
Sauer Paul F Md is a Pediatric Plastic Surgeon facility at 840 Montclair Road in Birmingham, AL.


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This is the Animal Description Header
; Cassie is a house trained, openly friendly girl, who rides well in the car, and gets along with other dogs. She is an active and happy girl, but has had some trouble in the past with adjusting to new people coming into the home, once she feels bonded with her family. We have not seen this behavior at all here at the sanctuary, and we have known her for quite some time now, but we do want to let adopters know this, as the behavior did cost her the family she was misguidedly trying to protect. This never happened while out and about in public, and in these situations she is very well mannered and social. We are looking for an adult home for Cassie, with folks who will be willing to work on this issue should it arise again. She really is highly bonding, cuddly and slightly goofy girl. In her next home she will however need someone to teach her that they do not need her to protect them from the dangers' of visiting friends, or to go settle in a different room when they have visitors.
; Cassies original bio, before she was returned for nipping a stranger inside her home: Social, nicely mannered, great in the car, great in a crate, good on leash, great with other dogs, though not a submissive dog. Cassie (formerly Cayenne) is spicy, and she can move, but she is a good family dog, friendly and happy, and eager to have a home!
; She is smart, agile, sweet, and definitely part Husky! She needs a well fenced yard. She will need to bond well before going off leash, but she is smart and people social, and very good! Great with other dogs - but not a pushover. A terrific dog. Not for the faint of heart, or first timers necessarily. She is house-trained and well mannered.
; If you would like to learn more about this very loving girl who craves another chance at a forever home, please send applications to firstname.lastname@example.com
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It was a learning process for both Milo and Lynne, his "seeing eye person". Lynne developed a series of taps to communicate with Milo. A tap on the left or right flank would instruct Milo which direction to go. And a tap on the rear meant 'stop'. In the park, Milo's feet read the ground like Braille, where he bounded around in circles with his nose in the air, barking with joy.
Given a chance to live, Milo became a happy, beloved dog. The experience with Milo led Lynne to learn about other animals who needed a chance - abandoned and stray dogs and cats who fill city shelters - which led to the founding of the nonprofit no-kill sanctuary: The Milo Foundation.
After a full and happy life, Milo passed away in August of 1998. He was the perfect spirit and namesake for a sanctuary dedicated to saving the lives of creatures who deserved, like Milo, a chance at a good life.
Today, The Milo Foundation is an established 501(c)(3) nonprofit, no-kill organization providing an alternative for homeless pets throughout Northern California, through education, adoption services, and providing sanctuary for animals until permanent homes can be found. Founded in August of 1994, The Milo Foundation is located on two hundred and eighty-three acres in Mendocino County - offering lots of room for the animals to run and play. Milo houses cats, dogs, puppies and kittens - occasionally farm animals and other domestic creatures find their way to the sanctuary.
Thank You!
Your message has been sent to Milo Foundation.
You'll receive a copy, too, at to help you keep track of which pets you've inquired about, and which shelters and rescues you've emailed.
NOTE: Some shelters have physical locations you can visit; some of these shelters may only have pets for a limited time, so please do not wait for a reply—just go visit the shelter! Other organizations are rescue groups run by busy volunteers who may take a while to reply. You can find information about the shelter or rescue group caring for this pet, and their adoption procedures, on the pet's details page on Adopt-a-Pet.com.


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Why worry about code visibility?
Many of the articles here are agonising about the information (code) gaining or losing "value" through the transaction. This is irrelevant. Who cares? The developer wants to develop. Users of his code want a new feature. He develops it, they pay him.
The point is that the developer is getting paid for doing useful work. The code could be open source and available right throughout the process, or only at the end. Doesn't matter.
Selling licenses sours the relationship between user and developer, because of the zero unit cost of software. Distributing entirely free software sours the relationship between the developer and his landlady.
The Ransom Model is a very good way to engage in a more productive, mutually beneficial relationship.
Over the last year we've developed an application which supports the whole process - managing user requests, issuing proposals, receiving votes and comments, a review process, surveys, news, etc. etc. - www.rap-x.com (http://www.rap-x.com/) .
A tool for securing DNS communications between a client and a DNS resolver.
A polyhedral extraction tool (PET).


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(Washington – September 15, 2011) Rep. Frank Guinta (NH-01) released the following statement after today's passage of H.R. 2587, The Protecting Jobs From Government Interference Act. It was approved in a 238-186 vote and now goes to the U.S. Senate for consideration:
"This bill will help create jobs and put more Americans back to work. It does that by removing burdensome regulations that allow the National Labor Relations Board to order the closure or relocation of American workplaces. The federal government shouldn't have the ability to capriciously intrude into the affairs of the private sector by dictating where a private business can establish its workforce. That's not only bad government, it's bad business, too, because it leaves companies facing uncertainty and unpredictability. This important legislation removes barriers to job growth and restricts the federal government's intrusion into the private sector."
Background: Earlier this year, the NLRB filed a complaint against the Boeing Company for creating work in South Carolina and sought to force Boeing to transfer the work to a unionized facility in Washington.
H.R. 2587 amends the National Labor Relations Act to prohibit the NLRB from ordering any employer to relocate, shut down, or transfer employment under any circumstances, and further eliminates an extreme enforcement remedy. It also preserves more than one dozen alternative remedies to hold employers accountable for unlawful labor practices and limits the NLRB's authority in all cases that have not reached a final adjudication before the board. Furthermore, H.R. 2587 fosters a positive environment for job creators to develop their businesses in the state that offers the best opportunities for growth and job creation.


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2017 And Still No Really Big Earth Shaking Medical Breakthroughs
Here we are going into 2017 and still no really big earth shaking medical breakthroughs, none that I've been aware of leastways. Disease is still with us as is AIDS, Cancer and the big diseases and Chemo Therapy is still "Death In A Bottle". Extraterrestrial space aliens still haven't come forward and went public, nor given us any really useful technology. Self-driving cars are still in the experimental stage, nor has the flying car become a practical reality, & economic collapse or WW 3 still hasn't happened. Scientist have now discovered the so called "Element 115" 2003 which Bob Lazar first spoke of in the 1980's and "supposedly" at that time was nothing but a hoax and Bob Lazar was nothing more than a crackpot. Transparent Aluminum first talked about in the movie Star Trek The Voyage Home also 1980's is now a science fact, there are no aliens from outer space & officially UFO's still don't exist. No one quite knows what is going to happen when Mr. Buzzard Elect takes office, and that's if the Buzzard even does take office (and no I didn't care or vote for that "female demon creature" who won the popular vote either). Most Americans are royally POed because they feel Russia rigged and/or meddled in the election, but feel it's perfectly OK for the US to topple, assassinate and/or meddle in the elections and affairs of governments in other countries, extremely hypocritical if you ask me.
The Department Of Veterans Affairs is still just as corrupted as it's even been.
And in the words of one Sonny & Cher "The Beat Goes One"
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text: The "Handy Light Part 2" Icon Set will be accompanying the "Handy Light" icons. This set includes graphic symbols for various electronic devices, with many of their operational functions, in addition to a few weather icons. The set contains 40 icons in 16x16px, 24x24px, 32x32px, 48x48px, 64x64px and 128x128px sizes, as PNG, ICO and ICNS file formats.


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New York? What's the point?
Dan Doctoroff
With Manhattan's famous skyline as their backdrop, Mayor Michael Bloomberg and Gov. George Pataki greeted runners on the bridge as they prepared to send the 600-page bid to the International Olympic Committee in Switzerland before Monday's deadline.
The bid details every aspect of the city's proposal, including security plans, environmental issues, transportation concerns and a financial plan. It will be available to the public next Wednesday.
Bloomberg, who has linked his political legacy with the city's Olympic pitch, said the games would bring $12 billion of economic activity and create 135,000 jobs.
"We're going to turn it up a notch and, for the next eight months, we're going to work harder than ever to get the Summer Games for 2012 right here where they belong," Bloomberg said.
Bloomberg described how the city's five boroughs would accommodate the Olympics, with mountain biking at the Fresh Kills landfill on Staten Island, swimming and diving in Willliamsburg, Brooklyn, baseball in Yankee Stadium in the Bronx, sailing off the Rockaways and the opening and closing ceremonies in a proposed new stadium on the Hudson River.
The mayor's plan for a West Side Stadium, which would be home to the NFL's Jets, faces strong opposition from neighborhood groups and other arena owners. The uncertainty surrounding the stadium plan, which would cost an estimated $1.4 billion, may complicate the city's Olympic hopes.
Bloomberg was flanked by New Yorkers waving flags from countries around the world and former Olympians and Paralympians flashing their medals.
"I think it would be great for the city," said Jason Read, who wore the gold medal he won for rowing in Athens. "There's no other place in the world as diverse as New York."
Pataki agreed.
"Every single country will have a built-in rooting section of New Yorkers rooting for that country," Pataki said. "This great city can host anything better than anybody else."
New York is competing for the 2012 games against London, Madrid, Moscow and Paris. The host city will be announced in July 2005.
Contributing: Devlin Barrett, Associated Press


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1. Submit a photo of yourself that shows us the freedom you feel from working online at Elance. Photos must be horizontal and should be taken with a 5-megapixel camera or higher. Photos should not contain pictures of your computer—we want to see photos that demonstrate your lifestyle! They should not contain added text or illustrations.
2. Between August 19, 2013 and 11:59 pm PDT September 1, 2013, submit your story on our Elance Facebook Contest Page. Photos must be submitted by 11:59 pm PDT on September 1, 2013. Throughout 2013, we will be featuring submitted photos on one or more of the following: the Elance Facebook Page, Elance Google+ Page Elance website, Elance newsletter, Elance homepage and the Elance Inspiration Center.
3. A panel of Elance judges will choose twenty-five (25) finalists. The final winners will be chosen by public vote. There will be one (1) Grand Prize winner, one (1) second place winner and one (1) third place winner. The winners will be announced by Elance on September 11, 2013.
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Prizes will be awarded to contestants with the top three (3) stories, as determined by public vote. A team of Elance judges will select twenty-five (25) finalists based on creativity, photo quality and alignment with Photo Contest theme: Freedom Through Freelance. One (1) Grand Prize winner will receive $1,00 cash and have their photo featured on the Elance Facebook Cover Photo. The second place winner will receive $500 dollars and third place will win $250. The (23) honorable mention winners will receive $25 Amazon gift cards.
1. ELIGIBILITY: NO PURCHASE NECESSARY. Elance's Freedom Through Freelance Photo Contest (the "Contest") is open only to individuals who are, as of January 21, 2013, at least 18 years of age and have reached the age of majority in the jurisdiction within which they reside at time of the start of the contest, and have an Elance account in good standing. Entrants must have Internet access during the duration of the contest to participate. Entrants must also be the rightful owner of the e-mail address that is linked to the specific social media account use during Entrant's submission. Employees, directors and officers, and their immediate families (spouse, parents, children, siblings, and their respective spouses), and their respective household members, of Elance, Inc. ("Elance"), its affiliates, subsidiaries, and divisions, and advertising and promotion agencies are not eligible to enter. All federal, state and local laws and regulations apply. Void where prohibited by law.
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Stories must be in English and meet the technical specifications to be uploaded on the Facebook Contest Page. Proof of submission does not constitute proof of receipt. If more than one entry is received per person, only one entry will be eligible to be deemed a winner for the Contest. Only one prize allowed per contestant.
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3. DETERMINATION OF WINNER: Between August 19, 2013 and September 1, 2013, Elance will accept photo submissions. Twenty-five (25) finalists will be chosen by a panel of Elance judges based on the aesthetic quality and creativity of their photo submission and how compellingly their photo reflects the Freedom Through Freelance theme. The final winners will be chosen by a vote that will be conducted on the Elance Facebook Contest Page. Voting will be open to the public. The judges' decisions in the selection of the finalists and the voters' decision in the selection of the grand prizewinners are final. All judgments are in the sole discretion of Elance.
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Attempting to Visualize the Synoptic Problem
by James Dowden
Over at the Jesus Blog, there's been a lively discussion (and now a poll!) on whether Farrer theorists are still in a minority. I thoroughly expect that we are, and so I'll preëmptively start harping on about why we're right again.
Part of the problem is perception: Luke's order's being different from Matthew's order gets mentioned frequently in discussions of the Synoptic Problem. What is less often mentioned is that Matthew is not simply Mark with a few discourses interpolated, but radically reörders the early part of Mark.
This reördering is incredibly difficult to visualize, but I've had a go at it below. One of the most difficult decisions was not to expand the discourses (although there are plenty of interesting things going on within them) and focus only on the surrounding narrative. It should hopefully be pretty self-explantory, but here's a brief key in case it isn't:
- BLUE – Matthew copying Mark in order
- GREY – Marcan material omitted by Matthew
- BLACK – Matthew's non-Marcan material
- GOLD – Material Matthew has redeployed in discourse settings
- YELLOW-GREEN – The Call of the Disciples, merged by Matthew into their Commission
- RED – A massive block of material that Matthew has brought forward to various locations
- TURQUOISE – A minor consequential flip
- PURPLES – Doubletty stuff
So, on the basis of the Farrer Theory, Luke had three choices for which order to base his own on:
- Mark's order;
- Matthew's order; or:
- invent a completely new order.
As it happens, he generally went for option 1: Mark's order. It's easy enough to see why this is an appealing choice: that first Sabbath day at Capernaum is an incredibly powerful story, whereas Matthew's fronted Sermon to an unexplained crowd doesn't work particularly well. But this leaves an obvious problem: what on earth was Luke to do with anything he found appealing in all that material in black?
To be continued, maybe, if I can ever create a visualization of how the next step in gospel composition worked that isn't too intimidatingly large…
tl;dr: Q theorists are happy for Matthew to know and reörder Mark, but not for Luke to know and reörder Matthew. Hypocrites! They will be cast out to outer darkness, where there will be weeping and gnashing of teeth!