Spray Freeze-Dried Porous Microparticles of a Poorly Water-Soluble Drug for Respiratory Delivery

Abstract

Particles of poorly water-soluble drugs were prepared to develop a dry powder inhaler (DPI). Spray freeze-drying (SFD) technique using a four-fluid nozzle (4N), which has been developed by authors, was applied in this research. Ciclosporin and mannitol were used as a poorly water-soluble model drug and a dissolution-enhanced carrier, respectively. The organic solution of ciclosporin and aqueous solution of mannitol were separately and simultaneously atomized through the 4N, and the two solutions were collided with each other at the tip of the nozzle edge. The spray mists were immediately frozen in liquid nitrogen to form a suspension. Then, the iced droplets were freeze-dried to prepare the composite particles of the drug and carrier. tert-Butyl alcohol (t-BuOH) was used as the organic spray solvent due to its relatively high freezing point. The resultant composite particles with varying drug content were characterized depending on their morphological and physicochemical properties. The particles contained amorphous ciclosporin and δ-crystalline mannitol. The characteristic porous structure of SFD particles potentially contributed to their good aerodynamic performance. A series of particles with a similar size distribution and different drug content revealed that the incorporation of mannitol successfully improved the cohesive behavior of ciclosporin, leading to enhanced aerosol dispersion. The dissolution test method using low-volume medium was newly established to simulate the release process from particles deposited on the surface of the bronchus and pulmonary mucosa. The composite with hydrophilic mannitol dramatically improved the in vitro dissolution behavior of ciclosporin in combination with the porous structure of SFD particles.Key words spray freeze-drying; liquid nitrogen; ciclosporin; porous particle; tert-butyl alcohol Inhalation is the most appropriate route to deliver drugs to treat respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis.1-3) This route directly targets the site of action and reduces the occurrence of systemic adverse effects. In addition, there is increasing interest in the use of pulmonary delivery to administer systemically-acting macromolecules, such as inhaled insulin product.4) The aerodynamic size of drug particles should be 5-6 µm or less for optimal airway deposition.5-7) However, particles in this size range have potentially cohesive property and tend to disperse poorly.One approach to achieve excellent inhalation delivery by simultaneously improving the micromeritic properties and reducing the cohesive properties of agents is to design spherical particles with relative large geometric diameters and low particle mass densities. Inter-particulate cohesion could be reduced by enlarging and spheronizing the individual particle, and aerosol performance could be improved by decreasing the weight of the particles, ultimately like soap bubbles. In particular, particle design focused on particle density has been specifically resear...

Numerical Study on Particle Adhesion in Dry Powder Inhaler Device

“…2 hydroxypropylmethylcellulose (HPMC) hard capsule (Shionogi Qualicaps, Nara, Japan) which was set into the device, followed by the powder suction for 5 s at a flow rate of 28.3 L/min. [28][29][30] The residual mass of the powder in the capsule was measured (n = 3).…”

1H NMR quantification of spray dried and spray freeze-dried saccharide carriers in dry powder inhaler formulations

“…The aerosolisation performance of DPI formulations is assessed by mass median aerodynamic diameter (MMAD) along with geometric standard deviation (GSD), fine particle dose (FPD) and fine particle fraction (FPF). MMAD is defined as the aerodynamic diameter at which 50% of total particles by mass (Niwa, Mizutani and Danjo, 2012) and GSD is expressed as a degree of an aerodynamic particle size distribution (Razavi Rohani, Abnous and Tafaghodi, 2014; Ali and Gary, 2015). FPD is defined as the amount of the delivered drug dose with less than or equal to 5.0 µm aerodynamic diameter.…”

“…FPF is defined as the mass fraction of the delivered drug dose with less than or equal to 5.0 µm aerodynamic diameter and used to characterise the lung deposition and efficiency of DPI formulations for systemic pulmonary application (Kramek-Romanowska et al, 2011;Depreter, Pilcer and Amighi, 2013;Ali and Gary, 2015;Peng et al, 2016;Mönckedieck et al, 2017). Particles collected from the low impactor stages (e.g., between 3 and 5) with less than or equal to 5.0 µm aerodynamic diameter generally represent the respirable-sized drug dose, whereas particles deposited in the higher impactor stages (e.g., throat and stage 1) represent the oropharyngeal deposition in the oropharynx region (Niwa, Mizutani and Danjo, 2012;Ali and Gary, 2015). In order to achieve therapeutic efficacy, the size of drug particles should be respirable (MMAD ≤5.0 µm) with low GSD indicating monodisperse particle size distribution to reach the desired deep lung regions for systemic pulmonary delivery and FPF should be high for drug aerosolisation efficiency (Kramek-Romanowska et al, 2011;Maltesen, Weert and Grohganz, 2012;Walters et al, 2014;Yang, Chan and Chan, 2014;Rahimpour, Kouhsoltani and Hamishehkar, 2014;Ali and Gary, 2015;Banga, 2015;Peng et al, 2016).…”

Control of the radial distribution of chemical components in spray-dried crystalline microparticles

“…However, it is known from electron micrographs that crystals may grow on the surface of droplets, eventually forming a crystalline shell. Several respiratory drugs have a known tendency to crystallize or have been formulated with crystallizing excipients (Patravale and Kulkarni 2004;Niwa et al 2012;Hoe et al 2014;Young et al 2015). In this case, the particle formation process includes a crystallization sub-process.…”