Porous silicon embedded in a thermoresponsive hydrogel for intranasal delivery of lipophilic drugs to treat rhinosinusitis

Abstract

Intranasal delivery is the most preferred route of drug administration for treatment of a range of nasal conditions including chronic rhinosinusitis (CRS), caused by an infection and inflammation of the nasal mucosa. However, localised delivery of lipophilic drugs for persistent nasal inflammation is a challenge especially with traditional topical nasal sprays. In this study, a composite thermoresponsive hydrogel is developed and tuned to obtain desired rheological and physiochemical properties suitable for intranasal administration of lipophilic drugs. The composite is comprised of drug-loaded porous silicon (pSi) particles embedded in a poloxamer 407 (P407) hydrogel matrix. Mometasone Furoate (MF), a lipophilic corticosteroid (log P of 4.11), is used as the drug, which is loaded onto pSi particles at a loading capacity of 28 wt%. The MF-loaded pSi particles (MF@pSi) are incorporated into the P407-based thermoresponsive hydrogel (HG) matrix to form the composite hydrogel (MF@pSi-HG) with a final drug content ranging between 0.1 wt% to 0.5 wt%. Rheomechanical studies indicate that the MF@pSi component exerts a minimal impact on gelation temperature or strength of the hydrogel host. The in-vitro release of the MF payload from MF@pSi-HG shows a pronounced increase in the amount of drug released over 8 h (4.5 to 21-fold) in comparison to controls consisting of pure MF incorporated in hydrogel (MF@HG), indicating an improvement in kinetic solubility of MF upon loading into pSi. Ex-vivo toxicity studies conducted on human nasal mucosal tissue show no adverse effect from exposure to either pure HG or the MF@pSi-HG formulation, even at the highest drug content of 0.5 wt%. Experiments on human nasal mucosal tissue show the MF@pSi-HG formulation deposits a quantity of MF into the tissues within 8 h that is >19 times greater than the MF@HG control (194 ± 7 μg of MF/g of tissue vs. <10 μg of MF/g of tissue, respectively).

Keywords: Corticosteroid; Human nasal mucosal tissue; Mometasone furoate; Poloxamer 407; Stimuli-responsive hydrogels.

Fig. 1.

Schematic showing preparation of the composite drug delivery system used in this work, consisting of porous silicon (pSi) particles loaded with the corticosteroid drug mometasone furoate (MF) and dispersed in a thermoresponsive polymeric hydrogel: (a) MF-loaded pSi is mixed with the tri-block polymer poloxamer 407 (P407) to form the MF@pSi-HG formulation. (b) the MF@pSi-HG composite exists as a liquid at storage temperature (4–8 °C), allowing it to be delivered as a spray. The liquid then solidifies to a gel when the temperature rises to a range corresponding to those found in the nasal cavity (30–34 °C). Gelation occurs because P407 transitions into a micellar form. (c) Digital photographs of the MF@pSi-HG system in a liquid state at 8 °C (storage temperature) and viscous-gel state at 32 °C (nasal cavity temperature).

Fig. 2.

(a) FE-SEM image of pSi particles showing plate-like particles with a characteristic unidirectional pore morphology. A plan-view image of a single particle, showing the pore texture, is shown in the inset. (b) Hydrodynamic diameter (from dynamic light scattering measurement) of representative pSi particles, showing an average particle size of 875 nm. Cryo-SEM images of the hydrogel system prepared using (c) free mometasone furoate (0.5MF@HG), and (d) MF-loaded pSi particles (0.5-MF@pSi-HG).

Fig. 3.

Temperature-dependent changes in storage (G’) and loss (G”) modulus of hydrogel formulations used to determine gelation temperature. The temperature versus storage and loss modulus of (a) blank hydrogel, (b) 0.1-MF@pSi-HG, (c) 0.2-MF@pSi-HG, and (d) 0.5-MF@pSi-HG. A sharp rise in the values of storage modulus is observed at the gelation temperature. The different coloured shaded regions in the graphs represent the three gelation stages. The blue coloured region (far left in all plots) corresponds to the liquid phase where the system behaves as a viscous liquid. The green region is the gel phase indicating gelation of the liquid. The red region indicates the formation of a strong and stable gel. The solid line in each graph represents the storage modulus and the loss modulus is presented by a dotted line (n = 3 ± SD).

Fig. 4.

Effect of changing shear rate on shear stress generated in (a) blank hydrogel, and formulations (b) 0.1-MF@pSi-HG, (c) 0.2-MF@pSi-HG, and (d) 0.5-MF@pSi-HG. At 8 °C, when the hydrogel is in its liquid state, changes in shear rate do not result in a significant change in shear stress while at 30 °C (temperature slightly above the gelation temperature), changes in shear rate result in a significant change in shear stress (n = 3 ± SD).

Fig. 5.

Temporal in-vitro release curves comparing cumulative release of mometasone furoate (MF) from hydrogel samples that contained either MF-loaded pSi particles or an equivalent mass of pure MF. Elution studies were performed at 34 °C, with the formulation contained in a sealed dialysis bag with simulated nasal fluid (SNF) in the receptor medium. The amount of hydrogel formulation in each dialysis bag was 500 μL. (a) cumulative MF release from 0.1-MF@HG (green) and 0.1-MF@pSi-HG (blue), (b) cumulative MF release from 0.2-MF@HG (green) and 0.2-MF@pSi-HG (black), and (c) cumulative MF release from 0.5-MF@HG (green) and 0.5-MF@pSi-HG (red). Data for each MF release time point is presented as mean ± SD of three independent experiments and was analysed by t-test comparing the difference of means of corresponding composite hydrogels and controls (* = P < 0.05).

Fig. 6.

(a) Lactate dehydrogenase (LDH) assay results evaluating toxicity of formulations applied to human nasal mucosal tissue, measured 5 days pre-exposure and 5 days post-exposure (including day 0). After exposure, tissues treated with hydrogel formulations containing MF-loaded pSi particles (0.1-MF@pSi-HG and 0.5-MF@pSi-HG) and SNF and SNF control solution were found to maintain LDH at baseline levels, while 1% w/v of ZnSO₄ in DMEM (positive control) elicited a significant cytotoxic and severe inflammatory response. All the data is presented as mean ± standard deviation of three repeats. Histology images of nasal mucosa tissue at 10× magnification (b) treated with 0.1-MF@pSi-HG, (c) treated with 0.5-MF@pSi-HG, (d) treated with 1% w/v ZnSO₄, (e) tissue treated with SNF, (f) untreated tissue. The scale bar is 100 μm and same for all histology images. The black arrows mark the olfactory epithelium and red arrows point to basal cells. All the tested control and test samples except for the 1 w/v % ZnSO₄ were nontoxic with comprehensive obliteration of the olfactory epithelium and basal cell layer.

Fig. 7.

Infiltration of mometasone furoate (MF) into human nasal mucosal tissue from pSi microparticle-containing hydrogels (0.1-MF@pSi-HG) and from control hydrogels containing free MF (0.1-MF@HG). Deposition of MF is quantified per gram of nasal tissue, measured 2 h, 4 h, 6 h, and 8 h after application of the relevant formulation. Both formulation types contain the same mass of MF. A gradual increase in the amount of drug deposited with time is observed for the 0.1-MF@pSi-HG formulation, while the 0.1-MF@HG control deposits a substantially lower amount (almost 19-times less) of drug per gram of nasal tissue over the 8 h span of the experiment. Data at each time point is presented as mean ± SD of three independent experiments and t-test indicated that difference of means of 0.1MF@pSi-HG and 0.1MF@HG at each time point was statistically significant (*** P < 0.0005).