Composition effects on the performance of dry powders for inhalation

Abstract

Chronic respiratory diseases, such as asthma, represent a significant global health issue. Symptoms are commonly treated through inhalation therapy, enabling the delivery of the active pharmaceutical ingredient (API) directly to the lungs. Pulmonary drug delivery offers several advantages, including reduced risk of systemic side effects and a minimally invasive route of administration.

Dry-powder inhalers (DPIs) are breath-actuated devices that contain the API in the form of a dry powder. Most formulations in these inhalers are adhesive mixtures, which consist of micronized API blended with larger carrier particles, mainly lactose. Excipient fines are sometimes added in order to improve the API dispersibility. The sum of the excipient fines and API content are referred to as total fines. Blending is an important process for the production of homogeneous adhesive mixtures. Mixers can be categorized into low, medium, or high-shear, based on the level of applied energy.

The aim of this project was to assess the effect of mixing conditions, as well as API and lactose fines content, on the performance of dry powders for inhalation. Budesonide was used as the API and lactose as the carrier. Formulations of 4 different compositions were pro-duced in the low-shear Turbula® blender at 1 and 3 hours and in the high-shear mixer at 2.5, 5, 9 and 14 minutes. The homogeneity of the prepared adhesive mixtures was verified and their bulk density was calculated. Additionally, the formulations were loaded into DPIs (No-volizer®) and their delivered dose, fine particle fraction (FPF), as well as mass median aer-odynamic diameter (MMAD) were determined using the Next-generation impactor (NGI). The powder morphology was also visualized on the scanning electron microscope (SEM).

The formulation with the lowest budesonide content (0.5 %) demonstrated the highest bulk density in both mixers, indicating better powder flow. Moreover, as the total fines increased from 6 % to 8 %, the bulk density decreased, while the delivered dose increased, due to better flow properties. The high-shear mixer resulted in higher FPF compared to the Turbula® blender for the formulations with lactose fines, regardless of mixing duration. In the Turbula® blender, the FPF increased at the mixing time of 3 hours compared to 1 hour for all batches.

The FPF data of the high-shear mixer were fitted to a proposed model correlating FPF with the mixing energy. The general trend was an initial increase in FPF, followed by a decrease at higher mixing energies, likely due to the increasingly prominent press-on forces. An ex-ception was the formulation with 0.5 % API, where the data were fitted to an exponential decrease. In addition, as the total fines increased, higher mixing energies were required to reach the highest potential FPF.

Popular Abstract

Asthma and other chronic respiratory diseases affect millions of people worldwide, including children. While they are uncurable, symptoms like difficulty breathing can be managed with proper medications. Inhalers deliver drugs straight to the lungs, reducing side effects. Inhalation therapy has many advantages and is much more convenient for patients when compared to injections. This study investigated how the composition and the processing method of the medications could improve inhaler performance.
Many inhalers, known as dry-powder inhalers, contain the drug in the form of a dry powder. This powder is a mixture of small drug particles and much larger carrier particles, most commonly lactose. Adding smaller lactose particles to this mixture can improve the efficiency of the inhaler. An inhaler is more efficient when a higher amount of drug reaches the lungs. The powder is produced by mixing the components together. Inhalers are becoming more popular for drug delivery. However, the relationship between the composition of the mixture and the efficiency of the inhaler has not been fully understood. The way the powder is mixed can also influence efficiency. So, it is important to research which drug percentages and which mixing conditions lead to more drug particles reaching the lungs. This could help improve the medications. The patients might also have to use them less often if more of the drug works instantly.
In this project, two types of mixers were used to produce powders with different composi-tions. It was found that more intense mixing improved inhaler performance when adding smaller lactose particles, even though mixing times were much shorter. One surprising result was that mixtures with small lactose particles increased the probability of drug reaching the lungs compared to mixtures that had a higher drug content. This is important to consider as these small lactose particles could improve inhalation therapy while decreasing the dose.
This work also studied how the powder particles were packed together. Loosely packed powders tend to flow poorly, which could decrease the dose reaching the lungs. The mixture with the lowest drug content had the most tightly packed particles. The powders were also studied under the microscope, where it was interesting to see the differences in appearance when adding smaller lactose particles.
The results also showed that for some powders it would be possible to find a mixing time and speed that maximizes the amount of drug particles reaching the lungs. It is important to note that overmixing had negative effects. Mathematical models were applied and they were found promising for predicting the relationship between mixing and inhaler efficiency. This can be useful for producing better mixtures while reducing the amount of experiments during research. Overall, adjusting the mixing time and the amount of small lactose particles could help improve inhalation therapy.

• author: Liati, Anna-Panagiota
• supervisor: Kyrre Thalberg
• organization: Food Technology and Nutrition (M.Sc.)
• course: KLGM06 20251
• year: 2025
• type: H2 - Master's Degree (Two Years)
• subject: Technology and Engineering
• keywords: inhalation, dry-powder inhalers, adhesive mixtures, lactose fines, mixing, fine particle fraction, pharmaceutical formulation
• language: English
• id: 9200595
• date added to LUP: 2025-06-17 12:52:28
• date last changed: 2025-06-17 12:52:28