(463c) Spray-Dried Amorphous Solid Dispersions for Nasal Delivery: Development, Characterization and Performance

Dry powder formulations for nasal drug delivery have advantages over liquid dosage forms, namely the improved stability and increased nasal residence time¹. For poorly soluble drugs, amorphous solid dispersions (ASDs) are an effective strategy to improve drug solubility, dissolution rate and, consequently, bioavailability^2,3. They consist of a molecular dispersion of a drug in one or more polymers. ASDs can be prepared by spray-drying and the polymers used can be selected with a dual function: stabilizing the amorphous form and increasing mucoadhesive properties, potentially increasing both dissolution and residence time of the formulation on the nasal cavity.

Given the potential of ASDs for nasal delivery of poorly soluble drugs, the aim of this work was to apply the solubility enhancing properties of ASDs to a poorly soluble model drug (piroxicam) while comparing two particle engineering strategies: spray-drying to obtain particles within the nasal size range of 10-45 µm¹, and agglomeration of spray-dried primary particles into chimeral agglomerates. Both techniques were benchmarked against equivalent physical blends.

METHODS

Piroxicam was selected as model drug, and polyvinylpyrrolidone/vinyl acetate (PVP/VA) and hydroxypropyl methylcellulose E3 (HPMC) as polymers. Spray-drying was performed, using ultra-sonic (USN) and two-fluid nozzle (TFN) to produce microparticles within the nasal size range and primary particles for agglomeration, respectively, in a Büchi model B-290 unit. Chimeral agglomerates were produced by vibrating primary particles in a sieve shaker equipped with 106 µm and 710 µm mesh size sieves. Agglomerates retained on top of the 106 µm sieve were collected. Physical blends were obtained by mixing neat polymer microparticles with piroxicam raw material in a Turbula blender. All formulations were produced at 20% (w/w) drug load.

The powders were characterized concerning their particle size (laser diffraction), morphology (scanning electron microscopy), water content (Karl Fisher) and solid state [differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD)]. Powders were filled in QUALI-V®-I capsules size 3. Aerodynamic performance was evaluated using a gravimetric 3-stage Andersen Cascade Impactor, equipped with a pre-separator and a 5-L glass expansion, using the active device Miat nasal insufflator. Stage 0, 2, and F were considered, simulating the intranasal passageways (aerodynamic particle size distribution [aerodynamic particle size distribution (aPSD) > 9.0 µm], gastrointestinal tract (aPSD from 4.7 µm to 9.0 µm) and respiratory system (aPSD < 4.7 µm), respectively⁴. The delivered dose during insufflation was determined using a Dosage Unit Sampling Apparatus, and drug quantification by High Performance Liquid Chromatography (HPLC). In vitro release testing (IVRT) studies were performed using Franz diffusion cells with a 5mL receptor compartment and a diffusion area of 0.636 cm². A dialysis cellulose membrane (MWCO ~ 12,000 Da) was used to separate donor and receptor compartments and simulated nasal fluid (SNF) (8.77 mg/mL NaCl, 2.98 mg/mL KCl, 0.78 mg/mL CaCl₂.2H₂O) at a pH of 6.0 was defined as the receptor solution. The receptor compartment was stirred at 600 rpm and maintained at 37ºC (assuring 32 °C at the membrane surface), mimicking in vivo conditions⁵. Formulations were applied directly in the donor compartment (5 mg) after weighing it onto a filter paper, followed by the addition of 50 µL of the SNF. Samples were withdrawn for 4 hours and analyzed by HPLC.

RESULTS

PXC microparticles were manufactured by spray-drying at 20% drug load and containing either HPMC or PVP/VA. When using a TFN, a considerable percentage of the particles had sizes below 10 µm. In order to manufacture particles within target particle size range, a 48 kHz USN was used due to its ability to produce larger and more uniform droplets. Spray-dried powders were successfully generated with yields above 39% and Dv50 between 28 and 45 µm. For the chimeral agglomerates, primary particles were manufactured by spray-drying using a TFN. Particle size fell in the desired range for agglomeration⁶ (Dv50 between 2 and 3 μm). Using either USN or TFN, particles containing HPMC had higher particle sizes and shriveled morphology, while PVP/VA particles were smaller and had a smooth surface. Chimeral agglomerates were obtained with yields above 80%. These agglomerates have been described as «chimeral» as their size is transient, being reduced during insufflation⁶.

DSC and XRPD analysis identified spray-dried microparticles and chimeral agglomerates as amorphous solid dispersions. However, HPMC particles showed recrystallization and melting events on DSC, suggesting higher susceptibility to phase separation and drug crystallization over time⁷. As the blends were manufactured by mixing crystalline drug with amorphous polymer, the resulting product shows a XRPD diffractogram with the amorphous pattern of the polymer and the crystalline peaks characteristic of the drug. Water content measurements identified high water contents for all formulations (>3.5% (w/w)) except for spray-dried microparticles of HPMC (1.55% (w/w)).

Aerodynamic performance studies showed that the fraction potentially retained in the nasal cavity (expansion chamber, pre-separator and Stage 0) was higher than 95% for all formulations (Fig. 1A). Delivered dose was high and reproducible for spray-dried microparticles of HPMC (97.5 ± 1.6 %). For the rest of the formulations, it was lower (51.6 to 75.1 %) and highly variable (standard deviations of 12.3 to 35.5 %), which can be due to the high water content values.

IVRT studies (Fig. 1B) evidenced that both the manufacturing strategy and the polymer have impact on the release behavior of the powder formulations. Spray-dried microparticles and chimeral agglomerates show increased amount of released piroxicam than the corresponding blends, most likely due to the amorphous state of the drug. Additionally, within each formulation manufacturing strategy type, powders containing HPMC showed increased mean percentages of drug released during the duration of the dissolution test (4h). This may be due to the enhanced ability of HPMC to inhibit drug precipitation in a supersaturated solution on the donor compartment, increasing the concentration gradient between both compartments for a longer period of time, and leading to a higher rate of diffusion.

CONCLUSIONS

ASD for nasal delivery were successfully produced using two different polymers at a 20% drug load, by three different manufacturing strategies. Microparticles within the nasal size range showed adequate aerodynamic performance and enhanced drug release properties compared with corresponding blends. For HPMC formulations, chimeral agglomerates, which require an extra manufacturing step, did not present advantages over spray-dried microparticles. Overall, the results support that the HPMC spray-dried microparticles with a 20% drug load would be the lead formulation candidate for further in vitro and in vivo testing, due to the superior and least variable emitted dose and drug release performance. Future work includes mucoadhesion and permeation testing.

References

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Figure 1 – (A) Aerodynamic profile of powder formulations. (B) In vitro drug release profile of powder formulations. SDM – spray-dried microparticles; CA – chimeral agglomerates; PVP/VA - polyvinylpyrrolidone/vinyl acetate; HPMC - hydroxypropyl methylcellulose.