Dokument: The influence of the carrter surface characteristics on dry powder inhalation
| Titel: | The influence of the carrter surface characteristics on dry powder inhalation | |||||||
| Weiterer Titel: | The influence of the carrier surface characteristics on dry powder inhalation | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=16850 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20110111-111952-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Boshhiha, Antesar [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Urbanetz, Nora Anne [Betreuer/Doktorvater] Prof. Dr. Kleinebudde, Peter [Gutachter] Prof. Dr. Proksch Peter [Gutachter] | |||||||
| Stichwörter: | Dry powder inhalation,lactose, mannitol, salbutamol sulphate, carrier surface fines | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibung: | THESIS ABSTRACT
THE INFLUENCE OF CARRIER PARTICLE CHARACTERSTICS ON DRY POWDER INHALATION FORMULATION Respiratory diseases such as asthma and chronic obstructive pulmonary disease are treated with a range of drugs which may be delivered either systemically or by inhalation. Pulmonary delivery of active pharmaceutical agents via dry powder inhalers (DPIs) has been attracting much attention in recent years as an alternative to pressurized metered dose inhalers (MDIs). DPI formulations typically consist of either drug alone or drug blended with inert carriers that are FDA-approved for inhalation as lactose and mannitol in an ordered mixture. Upon aerosolization the powder formulation must deaggregate into fine drug particles in the 1-5μm range for effective pulmonary delivery. The use of carrier particles enhances drug particles flowability and increases the inhalation efficiency. The adhesion between drug and carrier particles, as well as the fine particle fraction generated from this ordered mixture, can be influenced by a variety of factors, including the surface properties of drug and carrier particles, drug to carrier ratio, carrier particle size, shape, mixing time and method, humidity and electrostatic behavior. However, according to literature, impacting dry powder inhalant performance, is most successful by targeting the surface topography of the carrier particles. In this study carrier particles of lactose and mannitol were used. The carrier surface was modified by wet decantation, addition and removal of carrier fines and storage at different relative humidities to improve drug particle separation upon inhalation. The modified carriers were mixed with salbutamol sulphate in a tumbling mixer. DPI formulation performance was examined by the assessment of the respirable fraction of the drug in vitro. The results obtained using preconditioned carriers as opposed to unconditioned carriers suggest that preconditioning could be advantageous or disadvantageous in terms of the performance of dry powder inhalation. | |||||||
| Quelle: | F SUMMARY
Dry powder formulations consist mainly of fine drug particles mixed with inert coarse carrier particles to aid the flow and dispersion of the fine drug particles. A number of different carriers have been used although lactose has been employed most frequently, because it is the most available safe excipient. This study introduces mannitol as a new alternative to lactose in order to avoid the lactose drawbacks. Carrier particles used in this study have a 112µm-140µm size range. The fine drug particles which consist of salbutamol sulphate were obtained by micronization using air jet milling in the current study. As micronized salbutamol sulphate might be affected by the milling process which may result in a crystal dislocation and high energetic surfaces, this study investigated the changes of the crystallinity of salbutamol sulphate particles. The drug particles were conditioned via storage at elevated relative humidities at room temperature for different time periods. The crystallinity of the conditioned drug particles was investigated using differential scanning calorimetry, X-ray diffraction and water vapour sorption. Additionally particle size and shape were also investigated using laser diffraction and scanning electron microscopy. The results indicated that the relative humidity as well as storage time has to be carefully controlled in order to obtain thermodynamically stable fine drug particles. Additionally, the micronized salbutamol sulphate must be conditioned minimally for two weeks at 52.8%RH to get stable crystallized salbutamol sulphate. The performance of dry powder formulations might be affected by the geometric and physicochemical properties of carrier particles, which include the carrier particle size, shape, electrical charge, surface texture, crystallinity etc. In order to modify the surface properties of the raw carrier materials, different powder compositions were formulated with the aim of studying the influence of the carrier surface on the in vitro deposition of the powder formulation. In this study lactose and mannitol carrier materials were stored at elevated relative humidities for 6 weeks and investigated with respect to the lactose and mannitol carriers which were not stored at elevated relative humidities. The results showed a decrease in the in vitro deposition due to the storage of the carrier materials at higher relative humidities up to 95%, which allowed the condensation of water vapour on the carrier surfaces and formation of solid bridges between carrier fines and the coarse carrier particles. This bridge formation results in an increasing of the carrier surface smoothness, which usually increases the adhesion forces between the carrier and drug particles as a result of the increased contact area. Subsequently, this results in a less dispersion of drug particles from the carrier materials upon inhalation. Another approach used to modify the surface properties of raw carriers was to remove the carrier fine particles with a novel wet decantation process. The carriers were subjected to successive washing processes with absolute ethanol and lastly with dichloromethane to prevent the solid bridge formation between the carrier particles. As a result the decanted carriers showed a reduced FPF in comparison with the raw carriers themselves, which was authorized to the increased carrier surface smoothness due to a decrease in the carrier surface micro-roughness. This increased carrier surface smoothness offers a higher contact area for the drug particles and stronger adhesion to the carrier material which subsequently reduces the drug particle detachment upon aerosolization and decreases the FPF. Additionally, other mechanisms can be encountered to explain the reduced FPF for example the removal of fine particles leads to an increase of free high energetic spots at the carrier surface which can be occupied with the added drug. This occupation results in higher adhesion forces between drug and carrier particle and reduced fine particle fraction. Carrier fines were added back to the cleaned coarse carrier (wet decanted carrier), which improves the FPF of the drug to a certain limit. Moreover, these results seem to be influenced by the amount of carrier fines added to the powder formulation. The improved FPF of salbutamol sulphate with increased concentration of added fines may be caused by the saturation of the active sites on the carrier surface and a reduction of the adhesion forces between drug and carrier particles. Although the addition of fines to the decanted carriers could not revert the fine particle fraction to the original value of the raw carriers. This may indicate that the added fines were not equal to the original fines which had been removed by wet decantation. Added carrier fines exhibit another size, shape, surface, energetic charge, etc. than the inherent fines. Another interesting approach was to increase the carrier roughness via addition of carrier fines to the raw lactose and mannitol carrier materials. This increased roughness may offer weaker adhesion forces with drug particles and subsequently enhanced in vitro deposition. This improvement in FPF could be attained to a certain limit of the added carrier fines and then any further increase of the amount of added carrier fines was accompanied by a decrease of the FPF. The mechanisms by which this decrease is driven, however, is controversially discussed in literature and include the hypothesis of mixed agglomerates formation, which possess strong adhesion forces between drug and fines resisting the break up in the air stream and autoadhesion layer structure formation, where the frictional drug removal is less likely, because the drug particles are embedded in the macro-waviness of the autoadhesion layer. In order to confirm the results obtained after smoothing the carrier surface materials by wet decantation, the lactose and mannitol carriers were subjected to compressed air treatment using the air jet sieving process. The use of compressed air was shown to produce a cleaner carrier surface when compared to that before treatment. Striping of carrier fines from the coarse carrier with compressed air produced more adhesion sites for drug particles. This would be expected to increase the overall particulate interaction between the drug and coarse carrier particles, which would in turn reduce the FPF of the drug. This reduction in the FPF reflects the validity of the wet decantation process used in this study. The results of this study clarify the role of the surface carrier fines and indicated that the increasing surface smoothness and/or roughness must be balanced to get an improved in vitro deposition from the dry powder formulations. However, the added or removed carrier fines must not affect adversely the carrier physicochemical properties. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 11.01.2011 | |||||||
| Dateien geändert am: | 14.12.2010 | |||||||
| Promotionsantrag am: | 05.11.2010 | |||||||
| Datum der Promotion: | 21.12.2010 |
