Resistance is Futile:The targeted delivery of antibiotics to the lungs

Tuberculose (TB) is een infectieziekte waar jaarlijks 1.5 miljoen mensen aan overlijden. Het behandelen van TB wordt bemoeilijkt door toenemende resistentie. In sommige landen zijn de helft van de patiënten resistent tegen de eerste keus middelen isoniazide en rifampicine. Resistentie kan doorbroken worden door meer geneesmiddel op de plek van infectie te krijgen. Maar de dosis die oraal of per infusie kan worden toegediend wordt voornamelijk beperkt door de bijwerkingen, meer toedienen kan deze verhogen tot een niet te dragen last. Een andere mogelijkheid is het lokaal toedienen van geneesmiddel op de plaats van infectie. Hierdoor komt er daar meer geneesmiddel, terwijl de bijwerkingen worden geminimaliseerd. Omdat TB voornamelijk in de longen voorkomt is toediening via inhalatie een goede mogelijkheid om deze lokale behandeling vorm te geven. Het toedienen van geneesmiddelen via inhalatie wordt op dit moment voornamelijk toegepast voor laag gedoseerde geneesmiddelen (< 2,5 milligram), antibiotica zijn echter hoog gedoseerde geneesmiddelen, tot wel driehonderd milligram. Om deze geneesmiddelen per inhalatie toe te kunnen dienen zijn nieuwe technieken noodzakelijk. Zo is er bijvoorbeeld geen ruimte voor de hulpstoffen die in laag gedoseerde geneesmiddelen worden toegepast. In dit proefschrift worden de verschillende aspecten voor het toedienen van hoog gedoseerde geneesmiddelen beschreven. Er is uitgebreid onderzoek gedaan naar het ontwikkelen van een inhalator voor isoniazide, wat een uitdaging was door groter wordende deeltjes. Als laatste is onderzocht of isoniazide, en het antibioticum amikacine, automatisch afgevuld konden worden in inhalatoren. Dit bleek hogere doses mogelijk te maken. De resultaten van dit onderzoek vormen een goed startpunt voor de klinische ontwikkeling van nieuwe behandelopties voor de bestrijding van TB

Automated Filling Equipment Allows Increase in the Maximum Dose to Be Filled in the Cyclops(R)High Dose Dry Powder Inhalation Device While Maintaining Dispersibility

In recent years there has been increasing interest in the pulmonary delivery of high dose dry powder drugs, such as antibiotics. Drugs in this class need to be dosed in doses far over 2.5 mg, and the use of excipients should therefore be minimized. To our knowledge, the effect of the automatic filling of high dose drug formulations on the maximum dose that can be filled in powder inhalers, and on the dispersion behavior of the powder, have not been described so far. In this study, we aimed to investigate these effects after filling with an Omnidose, a vacuum drum filler. Furthermore, the precision and accuracy of the filling process were investigated. Two formulations were used-an isoniazid formulation we reported previously and an amikacin formulation. Both formulations could be precisely and accurately dosed in a vacuum pressure range of 200 to 600 mbar. No change in dispersion was seen after automatic filling. Retention was decreased, with an optimum vacuum pressure range found from 400 to 600 mbar. The nominal dose for amikacin was 57 mg, which resulted in a fine particle dose of 47.26 +/- 1.72 mg. The nominal dose for isoniazid could be increased to 150 mg, resulting in a fine particle dose of 107.35 +/- 13.52 mg. These findings may contribute to the understanding of the upscaling of high dose dry powder inhalation products

Dispersibility and Storage Stability Optimization of High Dose Isoniazid Dry Powder Inhalation Formulations with L-Leucine or Trileucine

Tuberculosis is the leading cause of death from a single infectious pathogen worldwide. Lately, the targeted delivery of antibiotics to the lungs via inhalation has received increasing interest. In a previous article, we reported on the development of a spray-dried dry powder isoniazid formulation containing an L-leucine coating. It dispersed well but had poor physical stability. In this study, we aimed to improve the stability by improving the leucine coating. To this end, we optimized the spray-drying conditions, the excipient content, and the excipient itself. Using L-leucine, the tested excipient contents (up to 5%) did not result in a stable powder. Contrary to L-leucine, the stability attained with trileucine was satisfactory. Even when exposed to 75% relative humidity, the formulation was stable for at least three months. The optimal formulation contained 3% trileucine w/w. This formulation resulted in a maximum fine particle dose of 58.00 ± 2.56 mg when a nominal dose of 80 mg was dispersed from the Cyclops® dry powder inhaler. The improved moisture protection and dispersibility obtained with trileucine are explained by its amorphous nature and a higher surface enrichment during drying. Dispersion efficiency of the device decreases at higher nominal doses

Challenges for pulmonary delivery of high powder doses

In recent years there is an increasing interest in the pulmonary delivery of large cohesive powder doses, i.e. drugs with a low potency such as antibiotics or drugs with a high potency that need a substantial fraction of excipient(s) such as vaccines stabilized in sugar glasses. The pulmonary delivery of high powder doses comes with unique challenges. For low potency drugs, the use of excipients should be minimized to limit the powder mass to be inhaled as much as possible. To achieve this objective the inhaler design should be adapted to the properties of the API in order to achieve a compatible combination of the drug formulation and inhaler device. The inhaler should have an appropriate powder dosing principle for which prefilled compartments seem most appropriate. The drug formulation should not only allow for accurate filling of these compartments but also enable efficient compartment emptying during inhalation. The dispersion principle must have the capacity to disperse considerable amounts of powder in a short time frame that allows the powder to reach the deep lung. Last, but not least, the inhaler should be simple and intuitive in use, be cost-effective and exhibit accurate and consistent, preferably patient independent, pulmonary delivery performance

Streamlining Cross-Organizational Aircraft Development: Results from the AGILE Project

The research and innovation AGILE project developed the next generation of aircraft Multidisciplinary Design and Optimization processes, which target significant reductions in aircraft development costs and time to market, leading to more cost-effective and greener aircraft solutions. The high level objective is the reduction of the lead time of 40% with respect to the current state-of-the-art. 19 industry, research and academia partners from Europe, Canada and Russia developed solutions to cope with the challenges of collaborative design and optimization of complex products. In order to accelerate the deployment of large-scale, collaborative multidisciplinary design and optimization (MDO), a novel methodology, the so-called AGILE Paradigm, has been developed. Furthermore, the AGILE project has developed and released a set of open technologies enabling the implementation of the AGILE Paradigm approach. The collection of all the technologies constitutes AGILE Framework, which has been deployed for the design and the optimization of multiple aircraft configurations. This paper focuses on the application of the AGILE Paradigm on seven novel aircraft configurations, proving the achievement of the project’s objectives

Conceptualizing, researching and evaluating democracy promotion and protection

Digitised version produced by the EUI Library and made available online in 2020

Lembaran negara Republik Indonesia : keputusan presiden Republik Indonesia nomor 65 tahun 1980

312 p.; 20 cm