(703f) Surface Engineering of Inhaled Pharmaceutical Particles By Atomic and Molecular Layer Deposition
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 . 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 Î¼m, 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 Â°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.
- 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.
- KÃ¤Ã¤riÃ¤inen, T.O., M. Kemell, M. VehkamÃ¤ki, M.-L. KÃ¤Ã¤riÃ¤inen, A. Correia, H.A. Santos, L.M. Bimbo, J. Hirvonen, P. Hoppu, S.M. George, D.C. Cameron, M. Ritala, and M. LeskelÃ¤, Surface modification of acetaminophen particles by atomic layer deposition. International Journal of Pharmaceutics, 2017. 525(1): p. 160-174.
- 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(1â2): p. 116-122.
- 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.