The observation that beta amyloid (Aβ) fragments in Alzheimer’s disease (AD) brain promote a marked neuro-inflammatory response makes inflammation a target for new drug therapies. Epidemiological studies reported that long-term oral administration of nonsteroidal anti-inflammatory drugs (NSAID) to patients having rheumatoid arthritis reduced risk and delayed onset of AD. Among other NSAID, flurbiprofen also showed to lower Aβ42 in vitro and in mouse models of AD. However, despite encouraging results in a phase-II clinical trial, oral administration of R-flurbiprofen (Tarenflurbil®) failed to produce clinical benefit in a phase-III trial mainly because of insufficient drug passage to the central nervous system (CNS).
Nasal administration may enable drugs to access the central nervous system more efficiently than by systemic administration as it bypasses the blood-brain-barrier (BBB). Direct nose-to-brain drug transport can occur along the trigeminal and olfactory nerve terminations that are exposed at the surface of the olfactory region in the nasal cavity.
Formulation-wise, nasal drug solids are advantageous compared to liquids for their higher stability and for the improvement of the drug retention into the nose and transport across the tissue.
Thus, the aim of this study was to formulate and characterize in vitro and in vivo a nasal powder suitable for nose-to-brain delivery of flurbiprofen as anti-inflammatory for early management of Alzheimer’s disease.
Microparticles of flurbiprofen sodium were prepared by means of either the Nano Spray Dryer-90 and Mini Spray Dryer B-290 (Büchi) varying the feed solvent composition and the temperature to see the effect on yield of production and microparticle properties. Then, blends (50:50) of spray-dried drug microparticles with spray-dried excipient (mannitol-lecithin) microparticles were agglomerated by (1) vibration of the blend on a sieve stack (106 and 850 mm sieve’s mesh size) or (2) tumbling of the blends in a 100-ml glass pan with deflected wall. Drug content (HPLC), particle size and size distribution (laser diffraction), solid state properties (DSC, PXRD), morphology (SEM) and in vitro drug transport across rabbit nasal mucosa (Franz cells, 4 h experiment) were evaluated for both microparticlesand agglomerates.
Plasma and brain pharmacokinetic of flurbiprofen in rats after nasal administration of Nano spray-dried flurbiprofen sodium microparticles (6 mg dose as flurbiprofen acid) and agglomerates thereof with excipient microparticles (3 mg dose as acid) were determined in comparison with intravenous (i.v.) and intranasal (i.n.) administration of a drug’s aqueous solution (4.5 mg and 0.3 mg as flurbiprofen acid for i.v. and i.n. solution, respectively). UDS powder insufflator (Aptar) was employed as device for nasal powder delivery.
For the microparticles, the spray dryer equipment influenced the physico-chemical characteristics of the dried product and process yield. Smaller particle size and narrower size distribution as well as higher yields were obtained with the Nano spray drier (Dv,50: 5.7 ±0.4 mm and 10.4 ±1.2 mm; yield: 80% and 20% for Nano and Mini spray drier, respectively). Moreover, it was possible to process the drug at lower inlet temperature by the Nano equipment (40-70 °C and 120 °C for Nano and Mini spray drier, respectively).
The spray dryer influenced also the capability of microparticles to form the agglomerates, while the agglomeration method impacted on the yield (80% and 50% by tumbling and vibration, respectively). All the agglomerates had a lower flurbiprofen sodium content (15-47%) compared to the theoretical value (50%) due to partial de-mixing of the blend during the agglomeration. In vitro drug transport across rabbit nasal mucosa was superimposable for the microparticles and the agglomerates (around 5 mg drug permeated per cm2 tissue after 4 h).
In vivo, UDS device delivered efficiently both nasal powders, but with higher performance when combined with the agglomerates (emitted powder: 66 ± 10% and 83 ± 4% for microparticles and agglomerates, respectively). The administration of nasal powders (microparticles and agglomerates) resulted into rapid drug absorption (plasma Cmax within the first 10 min after administration) and enhanced drug transport to the brain compared to both i.v. injection and i.n. solution (1.2 ± 0.2 and 0.8 ± 0.2 mg flurbiprofen as acid/g tissue for microparticles and agglomerates, respectively; 0.63 ± 0.06 and 0.01 ± 0.002 mg flurbiprofen as acid/g tissue for i.v. and i.n. solution, respectively).
Georgia Valsami– National and Kapodistrian University of Athens
Dimitrios Rekkas– National and Kapodistrian University of Athens
Paola Russo– University of Salerno
Gaia Colombo– University of Ferrara