Spray-dried mucoadhesive microparticles based on S-protected thiolated hydroxypropyl-β-cyclodextrin for budesonide nasal delivery

Abstract

Budesonide (BUD) is used as first choice therapy for the treatment of allergic rhinitis, a chronic allergic-immune condition with an increased incidence in the pediatric population. The main problem of BUD nasal formulations is related to its poor aqueous solubility (S₀ = 5.03·10^-5 M), sometimes compensated by the administration of high doses of the drug. The ability of thiolated hydroxypropyl-β-cyclodextrin (HP- β -CD-SH, 100 mM) to increase the water solubility of BUD (S_HP- β_-CD-SH = 10.9·10^-3 M) more than pristine hydroxypropyl- β -cyclodextrin (HP- β-CD, S_HP- β-_CD = 4.3·10^-3 M) has been previously demonstrated. Considering that S-protected thiomers have the advantage of increasing the stability of thiols over a wide pH range prolonging their residence time at the target site, 2-mercapto-nicotinic acid (MNA) was used in this study to protect the free thiol groups on HP- β -CD-SH generating the corresponding S-protected cyclodextrin (HP-β-CD-MNA). Besides, given the increased stability and processability of HP-β-CD-MNA, mucoadhesive microparticles (MPs) were prepared via spray-drying of aqueous solutions of the inclusion complex HP-β-CD-MNA/BUD. MPs were morphologically and dimensionally homogeneous exhibiting an average diameter of 3.24 ± 0.57 µm. Over time these MPs formed larger aggregates with an average diameter of 10-50 μm, suitable for the design of intranasal delivery systems. Differential scanning calorimetry analyses revealed the absence of crystalline BUD from spray-dried complexes. Dissolution studies shown that spray-dried MPs dissolved quickly and the complexed drug was completely solubilized within the first 20 min of the dissolution process. Cell viability assay indicated that spray-dried complexes are safe. In vitro mucoadhesion studies on freshly excised porcine nasal mucosa showed a 1.4- and 2.3-fold prolonged mucosal residence time of HP- β -CD-SH/BUD and HP-β-CD-MNA/BUD in comparison to the unmodified cyclodextrin (CD), respectively. Rheological behaviour of spray-dried MPs complexes/mucus mixtures confirmed the results of the mucoadhesion studies, as the dynamic viscosity of the spray-dried inclusion complexes HP-β-CD-SH/BUD and HP-β-CD-MNA/BUD was 1.1-fold and 2.4 fold increased in comparison to the unmodified HP-β-CD/BUD complex. According to these results, MPs comprising HP- β -CD-MNA/BUD might be a promising tool for nasal delivery of poorly water-soluble corticosteroids such as BUD.

Keywords: Allergic Rhinitis; Budesonide; Hydroxypropyl- β -cyclodextrin; Microparticles; Mucoadhesion; Nasal delivery; Spray-drying; Thiomers.