Spray Dried Particles for Inhaled Delivery of Protein Therapeutics
(2026) KLGM16 20261Pharmaceutical Technology (master)
Food Technology and Nutrition (M.Sc.)
Biotechnology (MSc)
Biotechnology (M.Sc.Eng.)
- Abstract
- Protein therapeutics need to be formulated into an amorphous solid state to be stabilized, and this is efficiently done by spray drying together with a sugar matrix excipient. The characteristics of the produced powder are strongly dependent on process parameters, and therefore, spray drying offers the possibility of advanced particle engineering. In this thesis, trypsin was spray dried as a model protein together with trehalose and L-leucine to form inhalable powders with focus on sustained protein activity. In a pre-study, 5% trypsin was spray dried in 50-80°C outlet temperature with 0, 10 and 20% leucine, then in the main study, 5 and 10% trypsin were formulated with the different amounts of leucine with an outlet temperature of 60°C.... (More)
- Protein therapeutics need to be formulated into an amorphous solid state to be stabilized, and this is efficiently done by spray drying together with a sugar matrix excipient. The characteristics of the produced powder are strongly dependent on process parameters, and therefore, spray drying offers the possibility of advanced particle engineering. In this thesis, trypsin was spray dried as a model protein together with trehalose and L-leucine to form inhalable powders with focus on sustained protein activity. In a pre-study, 5% trypsin was spray dried in 50-80°C outlet temperature with 0, 10 and 20% leucine, then in the main study, 5 and 10% trypsin were formulated with the different amounts of leucine with an outlet temperature of 60°C. The produced particles were close to spherical where the protein introduced a wrinkled surface, and leucine created a velvet shell of crystals around the particle. The preserved protein activity was generally high and did not vary substantially with outlet drying temperatures between 50-80°C. However, a higher amount of leucine in the formulation showed a higher preserved protein activity, both directly after spray drying and after storage under humid conditions. The geometric equivalent sphere particle size was evaluated using laser diffraction particle size analysis, which showed particles in suitable range for inhalation. The aerodynamic particle sizing showed slightly larger particles which is anticipated because the density is above one. But the fine particle fraction (FPF) was high with most formulations reaching 70-80%. It is also shown that both a higher protein and leucine content increases aerosolization and FPF in higher relative humidity (75%). DSC analysis showed two glass transitions between approximately 50-70°C and slightly below 120°C, indicating two amorphous phases and a possible stability issue by the low glass transition. (Less)
- Popular Abstract
- Biological drugs, including for example proteins, are generally administered as injections today, which is both invasive and often inconvenient for the patient. What if these drugs could be inhaled instead? The potential covers both drug delivery for specific treatment of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and lung cancer, as well as treatment of systemic diseases such as diabetes.
The reason why biological drugs are generally injected today, is primarily because of stability issues, they are easily broken down, and their large size, that makes it harder for them to be absorbed into the blood and tissue where we want the effect. The lungs are designed for efficient uptake of oxygen... (More) - Biological drugs, including for example proteins, are generally administered as injections today, which is both invasive and often inconvenient for the patient. What if these drugs could be inhaled instead? The potential covers both drug delivery for specific treatment of lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and lung cancer, as well as treatment of systemic diseases such as diabetes.
The reason why biological drugs are generally injected today, is primarily because of stability issues, they are easily broken down, and their large size, that makes it harder for them to be absorbed into the blood and tissue where we want the effect. The lungs are designed for efficient uptake of oxygen from the air, and this can also be used for efficient uptake of drugs. However, the design of the drug product for this to work, is not completely straightforward. For efficient drug delivery through the lungs, the inhaler device needs to be able to form a cloud of powder in the air, for you to be able to even breathe it in. This means that the powder particles cannot be sticking together or sticking to the container it comes in. Other than that, the powder particles need to reach the deep lungs, and to do that, each particle needs to be really small. Too large particles will just impact in the throat, get swallowed, and the drug will be broken down in the gut.
Traditional inhalable drugs are often produced in small particles using milling, but these rough conditions would destroy any biological drug. Instead, the small particles can be produced using a technique called spray drying. Here, we can dissolve the drug and the other needed ingredients in for example water, then spray this solution into hot air that evaporates the water, and the only thing left is the solid drug and other ingredients in very small particles that form a powder. But can the hot drying air lead to degradation of the proteins? This project found that the relatively high drying temperatures did not in fact lead to a substantial loss in protein activity, which reflects the drug efficiency, and at the same time, very small particles could be produced, making them suitable for inhalation. One of the advantages with this method is that the particle characteristics can be controlled by different settings in the spray dryer.
Another advantage is that the dry state offers stabilization of the protein. The most important additional ingredient in this project was a sugar, trehalose, that was used as a matrix for the solid state of the drug. However, the dry powder produced is also very sensitive to humidity, making storage harder, and we all know that drugs need to be able to sit in our cabinets or be carried around and still work when we need it.
Both the protein activity and the moisture sensitivity could also be enhanced using L-leucine in the drug product. L-leucine is a natural amino acid that forms a shell around the core of the particle, protecting the drug efficiently. It was also shown that the drug product with the highest amount of L-leucin, showed the highest protein activity after storage in high humidity. More leucine also led to slower crystallization of trehalose, increasing the stability of the product.
The spray drying technology for inhaled particles is very much still under development but there is a large potential that in the near future, we can inhale more advanced drugs than we can today, making life for patients easier as well as making side effects a smaller problem. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/student-papers/record/9234588
- author
- Ahlbom, Tilda LU
- supervisor
-
- Anna Fureby LU
- Kyrre Thalberg LU
- organization
- course
- KLGM16 20261
- year
- 2026
- type
- H2 - Master's Degree (Two Years)
- subject
- keywords
- Dry powder inhalation, Spray drying, protein drugs, L-leucine, Trehalose, Trypsin, Model protein, particle size distribution, aerodynamic diameter, geometric diameter, Specific surface area, Morphology, Aerosolization, Bulk density, Protein activity, Moisture resistance, Pharmaceutical formulation
- language
- English
- id
- 9234588
- date added to LUP
- 2026-06-17 14:09:10
- date last changed
- 2026-06-17 14:09:10
@misc{9234588,
abstract = {{Protein therapeutics need to be formulated into an amorphous solid state to be stabilized, and this is efficiently done by spray drying together with a sugar matrix excipient. The characteristics of the produced powder are strongly dependent on process parameters, and therefore, spray drying offers the possibility of advanced particle engineering. In this thesis, trypsin was spray dried as a model protein together with trehalose and L-leucine to form inhalable powders with focus on sustained protein activity. In a pre-study, 5% trypsin was spray dried in 50-80°C outlet temperature with 0, 10 and 20% leucine, then in the main study, 5 and 10% trypsin were formulated with the different amounts of leucine with an outlet temperature of 60°C. The produced particles were close to spherical where the protein introduced a wrinkled surface, and leucine created a velvet shell of crystals around the particle. The preserved protein activity was generally high and did not vary substantially with outlet drying temperatures between 50-80°C. However, a higher amount of leucine in the formulation showed a higher preserved protein activity, both directly after spray drying and after storage under humid conditions. The geometric equivalent sphere particle size was evaluated using laser diffraction particle size analysis, which showed particles in suitable range for inhalation. The aerodynamic particle sizing showed slightly larger particles which is anticipated because the density is above one. But the fine particle fraction (FPF) was high with most formulations reaching 70-80%. It is also shown that both a higher protein and leucine content increases aerosolization and FPF in higher relative humidity (75%). DSC analysis showed two glass transitions between approximately 50-70°C and slightly below 120°C, indicating two amorphous phases and a possible stability issue by the low glass transition.}},
author = {{Ahlbom, Tilda}},
language = {{eng}},
note = {{Student Paper}},
title = {{Spray Dried Particles for Inhaled Delivery of Protein Therapeutics}},
year = {{2026}},
}