(703f) Surface Engineering of Inhaled Pharmaceutical Particles By Atomic and Molecular Layer Deposition

Active pharmaceutical ingredients (APIs) and pharmaceutical excipients are typically small solid organic particles. The morphology and surface characteristics of both APIs and excipients play a crucial role in both their manufacturing and administration into the human body. On the one hand, the physical properties of pharmaceutical powders, e.g., particle size distribution, particle shape, density, and cohesiveness, as well as extrinsic factors such as moisture, temperature and triboelectricity strongly affect their bulk behavior (e.g., flowability, dispersibility and compactibility), and thus the manufacturing of dosage forms. For instance, poor powder flow can lead to weight variation and poor content uniformity during tabletting and capsule filling operations or poor dispersibility from dry powder inhalers. On the other hand, the size and shape as well as the crystal structure of pharmaceutical particles have a significant impact on their administration and bioavailability, and thus on the uptake by the human body. For example, particle size is crucial for pulmonary drug delivery, where particles with an aerodynamic diameter smaller than 5 µm are required to reach the targeted action sites of the deep lung. To achieve the desired inhalable particle size, the most commonly used method is micronization which delivers particles down to the micrometer or, in some cases, nanometer size. However, micronized particles are highly cohesive and moreover might present amorphous regions that crystallize over time in an uncontrolled manner. A growing amount of new inhaled APIs includes amorphous drugs, which are often very moisture-sensitive, as well as expensive and less potent drugs, which require improved flowability and aerosolization efficiency to meet the drug load requirements and to minimize their cost. Moreover, there is no commercially viable extended-release technique for inhaled drug particles. Therefore, there is an unmet need for novel solutions to provide surface modification of inhaled pharmaceutical powders that lead to improved processability and stabilization of solid state forms (e.g., amorphous, metastable, polymorphs, hydrates) and, most importantly, clinical benefits, e.g., controlled release of API from dosage forms.

Conventionally, improved flow properties, enhanced stability and tailored dissolution behavior have been achieved by placing a coating over the pharmaceutical particles. Nevertheless, due to the irregular shape and inhomogeneous surfaces of pharmaceutical particles, current technologies, based on both wet and dry synthesis, offer limited control over the coating thickness and poor drug loading efficiency, thus providing unsatisfactory performance of the final pharmaceutical formulation. Atomic layer deposition (ALD) is an established technique for the synthesis of thin films for various applications ranging from semiconductors to energy storage devices. Recently, it has been gaining attention in the pharmaceutical field to modify the single particle and bulk powder properties such as the drug release. Compared to the conventional methods of drug particle coating, ALD has a number of advantages: control over the amount of deposited material, conformality, and its solventless nature. A typical ALD process relies on sequential surface reactions of two gaseous precursors, which chemisorb on the solid substrate in alternate pulses, separated by inert gas purging. In doing so, ALD lends itself to the growth of multiple inorganic films, typically metal oxides, with exquisite thickness control at the sub-nanometer level.

ALD on pharmaceutical powders has been demonstrated by using rotary and fluidized bed reactors (FBRs) [1-3]. Despite being convenient systems for coating powders at the lab scale, rotary reactors are not suitable to manufacture the quantities of products required at the industrial scale. Instead, FBRs are inherently scalable, particularly if operated at atmospheric pressure. Moreover, FBRs are well-established technologies in the pharmaceutical industry. Therefore, ALD in atmospheric-pressure FBRs constitutes a scalable and cost-effective route to engineer pharmaceutical particles.

In this work, we demonstrate the use of ALD as a route to modify the properties of inhaled pharmaceutical particles, namely (i) dispersibility, (ii) stability to moisture and (iii) dissolution rate. We deposit ultrathin oxide ceramic films, namely Al₂O₃, TiO₂ and SiO₂, as well as hybrid inorganic-organic films on both API (e.g., budesonide and salbutamol) and excipient (i.e., lactose) particles, both crystalline and amorphous. The ALD process is carried out at ambient conditions in a fluidized bed reactor for a range of cycles from 10 to 50, using TMA/O₃, TiCl₄/H₂O and SiCl₄/H₂O as precursors for Al₂O₃, TiO₂ and SiO₂ ALD, respectively. The deposition strongly depends on the surface crystal structure of the particles. Time-of-flight secondary ion mass spectrometry and transmission electron microscopy reveal the deposition of uniform and conformal nanofilms on crystal surfaces, whereas uniform but non-conformal nanofilms are observed on amorphous surfaces [4]. The dispersion properties are evaluated both in the liquid and dry state. The ALD-coated particles exhibit considerably higher dispersibility in both water and ethanol solutions, thus suggesting higher bioavailability, than the uncoated ones. In-vitro aerosolization testing by the next generation impactor shows improved fine powder delivery (<5 μm, i.e., particle size range relevant for inhalation) and greatly reduced powder retention in the inhaler for the ALD-coated particles. The dispersion and aerosolization properties are retained even upon different conditions of temperature (25-40 °C) and relative humidity (60-75 %) over 3 weeks. Finally, in-vitro dissolution tests and cell absorption studies reveal more sustained release with increasing film thickness.

Nanoengineering of APIs for inhaled drug delivery is a novel application of ALD. Being a dry process at near ambient conditions, ALD provides an almost non-invasive platform to engineer surfaces of pharmaceutical particles, regardless of their shape, size and rugosity. Stabilization of sensitive particles and high energy solid forms with a conformal thin film is an attractive prospect for both drug product manufacturing and storage. Moreover, nanoscale films on inhaled particles can provide less cohesive powders with improved aerosolization properties, and thereby improved lung deposition, as well as at the same time powders with a tailored dissolution rate. This concept opens up exciting opportunities to produce more complex materials for targeted and controlled drug delivery.

References

1. Zhang, D., M.J. Quayle, G. Petersson, J.R. van Ommen, and S. Folestad, Atomic Scale Surface Engineering of Micro- to Nano- Sized Pharmaceutical Particles for Drug Delivery Applications. Nanoscale, 2017.
2. Kääriäinen, T.O., M. Kemell, M. Vehkamäki, M.-L. Kääriäinen, A. Correia, H.A. Santos, L.M. Bimbo, J. Hirvonen, P. Hoppu, S.M. George, D.C. Cameron, M. Ritala, and M. Leskelä, Surface modification of acetaminophen particles by atomic layer deposition. International Journal of Pharmaceutics, 2017. 525(1): p. 160-174.
3. Hellrup, J., M. Rooth, A. Johansson, and D. Mahlin, Production and characterization of aluminium oxide nanoshells on spray dried lactose. International Journal of Pharmaceutics, 2017. 529(1–2): p. 116-122.
4. Zhang, D., D. La Zara, M.J. Quayle, G. Petersson, J.R. van Ommen, and S. Folestad, Nanoengineering of Crystal and Amorphous Surfaces of Pharmaceutical Particles for Biomedical Applications. ACS Applied Bio Materials, 2019.