Dokument: DEVELOPMENT OF MICROPARTICLE - NANOPARTICLE POWDER MIXTURES FOR THE USE IN DRY POWDER INHALERS
| Titel: | DEVELOPMENT OF MICROPARTICLE - NANOPARTICLE POWDER MIXTURES FOR THE USE IN DRY POWDER INHALERS | |||||||
| Weiterer Titel: | DEVELOPMENT OF MICROPARTICLE - NANOPARTICLE POWDER MIXTURES FOR THE USE IN DRY POWDER INHALERS | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=12171 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20090721-101301-5 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | English, Middle (1100-1500) | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Mykhaylova, Viktoriya [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Urbanetz, Nora Anne [Gutachter] Prof. Dr. Kleinebudde, Peter [Gutachter] | |||||||
| Stichwörter: | Powder inhalers, nanoparticles, microparticles, salbutamol sulphate, salbutamol base, lactose | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | The use of inhaled drugs for the treatment of respiratory diseases, such as bronchial asthma, chronic bronchitis or chronic obstructive pulmonary diseases (COPD) has increased tremendously during the last decades. Compared with systemic therapy, aerosols have many clinical advantages. For example, the therapeutic effect can be achieved with a fraction of the dose needed when the drug is administered systemically. Thereby, the risk of extrapulmonary and systemic side effects is reduced. The onset of action is faster after pulmonary application. This is very important for drugs, like bronchodilators, which are used for the treatment of acute bronchospasm (Moren, 1993).
For many years, aerosol therapy was used mostly for the treatment of airways diseases. Lately, aerosols have been used for the treatment of extrapulmonary diseases like diabetes mellitus or cancer. Also the interest in the systemic therapy with peptide drugs, hormones and antibiotics increases (Lohrmann, 2005). It is of great advantage that the surface of the lung of the grown up person is ca. 100 m2 and works as a highly permeable membrane. The pulmonary application is free of pain. The problems with poor resorption and first pass effect can be avoided and the bioavailability of drugs may be increased. Drug delivery to the lung is not problem free. Some aerosol ingredients may cause irritation and bronchospasm. Not all patients are able to use available devices for inhalation properly. There are three main possibilities for the pulmonary application: metered dose inhalers, nebulisers and dry powder inhalers. The most frequently used delivery systems are pressurized metered dose inhalers. Also, the usage of dry powder inhalers is on the rise. The advantages of the latter are, that the formulation does not need environmentally harmful propellants, and active ingredients, which are usually instable in fluid media, can be used. Nebulisers may be used for aerosol generation also, but they are usually too large for the usage as portable devices (Moren, 1993). The main concern with most inhaled aerosols is the deposition at the desired location in the respiratory tract. The deposition is dependent on the particle size of the aerosol and breathing pattern of the patient. Particles may be too large to pass the oropharynx and larynx and to deposit in the deep parts of the lung. The optimal aerodynamic diameter of the particles must be between 1 µm and 5 µm. Larger particles stay in the upper airways, whereas smaller ones are be exhaled again. To ensure the arriving of the active ingredient powder at the site of action usually the powder has to be micronised. Micronised powders are usually very cohesive leading to poor flowability, mass uniformity upon dosing and redispersion, which cause the amount of the active ingredient in the low part of the lung to vary. In order to get an easy flowing powder, which is ready for use in dry powder inhalers, drug particles are often mixed with coarse carrier particles. The diameter of the carrier particles varies mostly between 50 µm and 200 µm. As carrier materials lactose, glucose or mannitol are reported to be in use (Steckel et al., 2004; Saint Lorant et al., 2007). Upon inhalation the drug particles must separate from the carrier in order to reach the alveolar part of the lung. The drug particle fraction, which is separated from the carrier particles during inhalation, is largely dependent on the interparticle interactions between drug and carrier. If the interactions between the two interacting partners are stronger than between the particles of the same fraction, the drug particles tend to stick on the carrier particles, ensuring thereby highly homogeneous free flowing interactive mixtures with good mass uniformity. It might be difficult to detach the drug particles from the surface of the carrier during inhalation due to high interparticle interactions. At the beginning of the inhalation process, Van der Waals and electrostatic forces play the dominating role. After the entrance of the powder in the mouth throat area and mixing with warm and humid air, the powder may start to gain water and capillary forces may increase immensely (Moren, 1993). If the interactions between the drug and the carrier are too weak, the particles tend to agglomerate with the particles of the same fraction resulting in the decomposition of the powder mixture. In order to control the amount of drug, which reaches the targeted parts of the lung several ideas, such as addition of fines or formation of “soft pellets”, which represent agglomerates of micronised drug particles were proposed and tested (Moren, 1993). Goal of this study is the evaluation of an innovative formulation approach for the use in dry powder inhalers, designed to work without coarse carriers using drugs coated with nanoparticles. Nanoparticles are used as spacers between drug particles, thus reducing interparticle interactions (Huber et al., 2003; Mykhaylova et al., 2006). To prove the viability of this concept, a model was chosen consisting of spray dried and micronised powders as the model substance for the active ingredient, and colloidal silicon dioxide (Aerosil® R972), as the model substance for the nanoparticles covering the drug particles. Mixtures of microparticles and nanoparticles were prepared by conventional mixing using the TURBULA® shaker mixer or by electrostatically supported mixing (Huber, 2001; Mykhaylova et al., 2006) using the high speed homogenator ULTRA TURRAX®. Amount of active ingredient presumably reaching the respiratory tract was determined by aerodynamic assessment of fine particles in vitro using the Next Generation Pharmaceutical Impactor (European Pharmacopoeia 6.0). Different methods to characterise the flowability of the mixtures were evaluated in order to obtain a measure for the uniformity of mass, as well as the uniformity of mass itself, using a multidose dry powder inhaler was, determined.The use of inhaled drugs for the treatment of respiratory diseases, such as bronchial asthma, chronic bronchitis or chronic obstructive pulmonary diseases (COPD) has increased tremendously during the last decades. Compared with systemic therapy, aerosols have many clinical advantages. For example, the therapeutic effect can be achieved with a fraction of the dose needed when the drug is administered systemically. Thereby, the risk of extrapulmonary and systemic side effects is reduced. The onset of action is faster after pulmonary application. This is very important for drugs, like bronchodilators, which are used for the treatment of acute bronchospasm (Moren, 1993). For many years, aerosol therapy was used mostly for the treatment of airways diseases. Lately, aerosols have been used for the treatment of extrapulmonary diseases like diabetes mellitus or cancer. Also the interest in the systemic therapy with peptide drugs, hormones and antibiotics increases (Lohrmann, 2005). It is of great advantage that the surface of the lung of the grown up person is ca. 100 m2 and works as a highly permeable membrane. The pulmonary application is free of pain. The problems with poor resorption and first pass effect can be avoided and the bioavailability of drugs may be increased. Drug delivery to the lung is not problem free. Some aerosol ingredients may cause irritation and bronchospasm. Not all patients are able to use available devices for inhalation properly. There are three main possibilities for the pulmonary application: metered dose inhalers, nebulisers and dry powder inhalers. The most frequently used delivery systems are pressurized metered dose inhalers. Also, the usage of dry powder inhalers is on the rise. The advantages of the latter are, that the formulation does not need environmentally harmful propellants, and active ingredients, which are usually instable in fluid media, can be used. Nebulisers may be used for aerosol generation also, but they are usually too large for the usage as portable devices (Moren, 1993). The main concern with most inhaled aerosols is the deposition at the desired location in the respiratory tract. The deposition is dependent on the particle size of the aerosol and breathing pattern of the patient. Particles may be too large to pass the oropharynx and larynx and to deposit in the deep parts of the lung. The optimal aerodynamic diameter of the particles must be between 1 µm and 5 µm. Larger particles stay in the upper airways, whereas smaller ones are be exhaled again. To ensure the arriving of the active ingredient powder at the site of action usually the powder has to be micronised. Micronised powders are usually very cohesive leading to poor flowability, mass uniformity upon dosing and redispersion, which cause the amount of the active ingredient in the low part of the lung to vary. In order to get an easy flowing powder, which is ready for use in dry powder inhalers, drug particles are often mixed with coarse carrier particles. The diameter of the carrier particles varies mostly between 50 µm and 200 µm. As carrier materials lactose, glucose or mannitol are reported to be in use (Steckel et al., 2004; Saint Lorant et al., 2007). Upon inhalation the drug particles must separate from the carrier in order to reach the alveolar part of the lung. The drug particle fraction, which is separated from the carrier particles during inhalation, is largely dependent on the interparticle interactions between drug and carrier. If the interactions between the two interacting partners are stronger than between the particles of the same fraction, the drug particles tend to stick on the carrier particles, ensuring thereby highly homogeneous free flowing interactive mixtures with good mass uniformity. It might be difficult to detach the drug particles from the surface of the carrier during inhalation due to high interparticle interactions. At the beginning of the inhalation process, Van der Waals and electrostatic forces play the dominating role. After the entrance of the powder in the mouth throat area and mixing with warm and humid air, the powder may start to gain water and capillary forces may increase immensely (Moren, 1993). If the interactions between the drug and the carrier are too weak, the particles tend to agglomerate with the particles of the same fraction resulting in the decomposition of the powder mixture. In order to control the amount of drug, which reaches the targeted parts of the lung several ideas, such as addition of fines or formation of “soft pellets”, which represent agglomerates of micronised drug particles were proposed and tested (Moren, 1993). Goal of this study is the evaluation of an innovative formulation approach for the use in dry powder inhalers, designed to work without coarse carriers using drugs coated with nanoparticles. Nanoparticles are used as spacers between drug particles, thus reducing interparticle interactions (Huber et al., 2003; Mykhaylova et al., 2006). To prove the viability of this concept, a model was chosen consisting of spray dried and micronised powders as the model substance for the active ingredient, and colloidal silicon dioxide (Aerosil® R972), as the model substance for the nanoparticles covering the drug particles. Mixtures of microparticles and nanoparticles were prepared by conventional mixing using the TURBULA® shaker mixer or by electrostatically supported mixing (Huber, 2001; Mykhaylova et al., 2006) using the high speed homogenator ULTRA TURRAX®. Amount of active ingredient presumably reaching the respiratory tract was determined by aerodynamic assessment of fine particles in vitro using the Next Generation Pharmaceutical Impactor (European Pharmacopoeia 6.0). Different methods to characterise the flowability of the mixtures were evaluated in order to obtain a measure for the uniformity of mass, as well as the uniformity of mass itself, using a multidose dry powder inhaler was, determined. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Technologie und Biopharmazie | |||||||
| Dokument erstellt am: | 21.07.2009 | |||||||
| Dateien geändert am: | 20.07.2009 | |||||||
| Promotionsantrag am: | 12.01.2009 | |||||||
| Datum der Promotion: | 25.05.2009 |
