(T1330-05-29) Selection of Excipients for Levodopa-Loaded Microparticles Prepared Using Spray-Drying

Purpose: L-dopa is the most effective symptomatic therapy used in the treatment of Parkinson’s disease. Administration of conventional oral Levodopa (L-dopa) is associated with dyskinesias thought to be caused by inconsistent or delayed drug delivery to the brain (1). Solid L-dopa delivered intranasally could, therefore, be a potential alternative that allows more consistent drug delivery directly to the brain. Intranasal delivery of spray-dried solid microparticles of L-dopa co-processed with bio-adhesive polymers can allow for prolonged residence time on the nasal epithelium, resulting in reduced mucociliary clearance. The objective of the present study was to select formulation excipients suitable for the preparation of L-dopa-loaded microparticles by spray-drying, having a volume-basis particle size distribution (PSD) ranging of 10-50 µm.

Methods: Four formulations containing different matrix polymers were tested in combination with L-dopa, and the total % solids-content of the feed-stock solution was determined (Table 1). Polymers were dissolved in deionized water using an ultrasonic bath. Following dissolution, L-dopa was mixed with the solutions using a vortex, owing to observed degradation of the drug on heating. Microparticles were prepared using a Yamato ADL 311S mini spray-dryer, equipped with a 0.7 mm spray nozzle. All solutions were fed at a flow rate of 8.2 mL/min and spray-dried using an inlet air temperature of 170°C, atomization pressure of 0.05 MPa, and exhaust speed of 0.41 m³/min. Microparticle PSDs were characterized on a volume basis using an Olympus light microscope to determine the Feret’s diameter from images obtained at 10x magnification and processed using ImageJ software(ij153-win-java8). The plume angle of microparticles that met PSD specifications was measured when formulations were sprayed from a dry powder insufflator (Model DP-4, Penn-Century), to confirm adequate flow properties in a commercial device.

Results: Microparticles prepared with 20% (w/w) Poloxamer 188 (F1) generated large agglomerates (Figure 1a), which was attributed to the melting of this polymer (T_m = 55^oC) at high inlet temperature used for spray-drying (170^oC). F2 replaced most of the poloxamer 188 with 15% (w/w) PVP K12 (T_g≈105°C), which resulted in less agglomeration of the spray-dried particles (Figure 1b). But the presence of 5% (w/w) poloxamer in the formulation led to the observed irregularly shaped microparticles, which were unsuitable for size characterization. F3 eliminated the poloxamer component, and contained only 15% (w/w) PVP K12, which resulted in large agglomerates (Figure 1c). Subsequent deliquescence of the PVP did not allow particle size characterization. When maltodextrin (T_g≈165°C) was combined with the PVP K12 (F4) spray-drying of feed-stock solutions containing 1% (w/w) L-dopa resulted in smooth, spherical microparticles (Figure 1d). Microscopy characterization of F4 microparticles (n≈5700) revealed a PSD ranging from 13-40 µm, having DV₅₀ ≈ 25 µm, and a span of 1.03 (Table 1 and Figure 2a). Having met PSD specifications, F4 microparticles were loaded into a commercial insufflator. The spray plume resulting from device actuation is captured in Figure 2b and 2c, and had a measured angle of 15-23°.

Conclusion: Spray-drying aqueous feed-stocks of L-dopa containing poloxamer 188 (F1 and F2) produced agglomerated microparticles, likely due to melting during processing. Spray-drying of aqueous poloxamer solutions is not suitable owing to the high temperatures required to evaporate the processing solvent. Spray-drying of PVP K12 (F3) generated large agglomerates, which rapidly deliquesced making them unsuitable for insufflation. Addition of the spray-drying aid maltodextrin (F4) to PVP K12 produced L-dopa-loaded microparticles that met size specifications. The measured plume angle of F4 sprayed from an insufflator device suggested adequate flow properties of the formulation. In general, spray-drying aqueous solutions requires excipients having high melting temperatures or glass transition temperatures to accommodate the processing temperature needed to remove the water.

References: 1. Paik J. Levodopa inhalation powder: a review in Parkinson’s disease. Drugs. 2020 Jun;80(8):821-8.


Table 1: Composition of L-dopa loaded SD microparticle formulation and particle size distribution.


Figure 1: Photomicrograph of L-dopa loaded SD microparticles showing that formulation F1, F2 and F3 (a, b, and c) generated agglomerated particles but F4 resulted in smooth and spherical non-agglomerated particles (d).


Figure 2: Particle size distribution of L-dopa loaded SD microparticles prepared from formulation F4 (a), Plume angle of spray-dried L-dopa loaded microparticles of F4 (b) Plume angle determination using ImageJ (c).